Treatment of insulin resistance syndrome and type 2 diabetes with pde9 inhibitors

专利摘要:
The present invention relates to a method of treating insulin resistance syndrome (IRS), hypertension and / or type 2 diabetes in a mammal comprising administering to the mammal a cGMP PDE9 inhibitor or a pharmaceutical composition thereof. The present invention also relates to the above therapeutic method wherein the cGMP PDE9 inhibitor is used in combination with other agents for treating IRS, hypertension and / or type 2 diabetes.
公开号:KR20040053210A
申请号:KR10-2004-7006251
申请日:2002-09-12
公开日:2004-06-23
发明作者:데이비드 알버트 프리버그；얼 마이클 깁스
申请人:화이자 프로덕츠 인크.；
IPC主号:

专利说明:

TREATMENT OF INSULIN RESISTANCE SYNDROME AND TYPE 2 DIABETES WITH PDE9 INHIBITORS}
[2] IRS as defined herein refers to the coexistence of two or more of hyperinsulinemia, dyslipidemia, hypertension, type 2 diabetes or impaired glucose tolerance, hyperuricemia or gout, pro-coagulation, atherosclerosis, and / or central obesity in a subject. it means. At the heart of IRS, also known as "syndrome X" and "metabolic syndrome" in the biomedical literature, there is a common feature of tissue resistance to the action of insulin. Biological dysfunction to this insulin is manifested in the metabolic and vascular effects of insulin. There is a monogenic syndrome of insulin resistance (IR), in which certain genes have been identified as the cause of insulin resistance (eg, Donohues syndrome), but this is relatively rare. In contrast, the more common presentation of the IRS is associated with obesity (particularly the abdomen) and appears to be polygenic.
[3] Adaptive responses to IR in subjects with IRS cause subject hyperinsulinemia. As IRS patients become progressively insulin resistant, they are clinically involved, including an increase in blood pressure and / or blood sugar and / or cholesterol and / or triglycerides and / or uric acid and / or factors that increase coagulation. The degree of change in the variable is indicated. When the clinical variable is sufficiently changed, the IRS patient may separately indicate a well recognized clinical condition or diagnosis.
[4] The condition may include type 2 diabetes, hypertension, hyperlipidemia or dyslipidemia, particularly hypertriglyceridemia, hyperuricemia or gout, and hypercoagulation (especially in blood vessels, abnormally high clot formation). Defined as trend). This clinical condition is a widely recognized risk factor for cardiovascular (coronary and cerebrovascular) diseases.
[5] It is difficult to assess the onset of IRS in the general population, due to the diversity of collective risk factors associated with IRS and the possibility that many IRS patients will not be detected because they have no external symptoms and no history of coronary heart disease, but at least Patient populations at risk of developing IRS are considered to include individuals with obesity, particularly central (abdominal) obesity. Obesity is a common problem in the industrial society and is associated with the clinical conditions mentioned above. Thus, the incidence of IRS can be very high. Consideration of only this potential patient group forms a large population that is potentially at risk of developing IRS complications. For example, in 1994 in the United States, 23% of the 20-74 age group had hypertension, which accounts for five deaths per 100,000 population (1997). In 2000, there will be an estimated 154,392,000 diabetics worldwide. Of these, 15,000,000 will be in the United States and 934,000 in the United Kingdom. In the estimated WHO countries in 1998, there were 51,948,000 patients with death and 7,375,000 deaths for both men and women, which constitute 13.7% of total deaths and occupy the highest position in the total deaths. In the estimated WHO countries in 1998, there were 11,668,000 diabetics for both men and women. Accordingly, there is a significant medical need for effective and safe oral therapy for the treatment of IRS and for the prevention of the development of the IRS and its clinical results.
[6] Resistance to the insulin effect is also observed in the reduction of the endothelial biological response to the vascular effect of insulin. In other words, insulin promotes relaxation of blood vessels, at least in part through the action of nitric oxide (NO). Nitric oxide produced in the endothelium stimulates cGMP production in blood vessels and relaxes or dilates blood vessels. Opening these vessels allows more blood to flow, which is particularly important when more blood flow is required for important organs such as the heart. IR patients have demonstrated reduced NO release from the endothelium. The reduced release of NO is not only from insulin, but also from other important vasodilators such as acetylcholine. This so-called "endothelial dysfunction" contributes to risk factors for cardiovascular disease associated with IRS. The vascular effect of insulin contributes to the effect of insulin on controlling metabolism, particularly but not limited to glucose metabolism.
[7] NO also directly affects glucose uptake by skeletal muscle. In other words, in vitro treatment with NO-donor material such as nitropurside or cGMP analogues increases glucose uptake (delivery by GLUT4 sugar transporter). Such vasodilation-independent pathways are incorporated herein by reference in GJ Etgen, DA Fryburg and EM Gibbs in Diabetes , 46 , 1997 pp. 1915-1919. Taken together, NO and cGMP have direct target tissue (skeletal muscle) and vascular action that affects, mediates, or mimics the action of insulin.
[8] Additional effects of NO free failure by the endothelium include increased vascular smooth muscle cell (USMC) growth, proliferation and migration, which is a key step in atherosclerotic plaque formation that can lead to seizures; Increase in platelet aggregation and adhesion; Increased lipid peroxidation and effects on inhibition of cell adhesion molecule expression, including vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM), E-selectin. Endothelial NO free failure also affects the activity of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and the production of monocyte chemoattractors through the reduced activity of the transcriptional activator nuclear factor kappa B. The effect on the platelets is also cGMP driving.
[9] Finally, there is an example in which the treatment of factors contributing to the IRS or the treatment of the IRS itself improves many of the clinical conditions that seem unrelated at first glance. For example, pharmacotherapeutics that induce diet alone or weight loss will reduce blood pressure, blood sugar and triglycerides. Drugs designed to improve insulin sensitivity can also advantageously alter blood pressure, lipids and blood sugar.
[10] Successful diagnosis and treatment of IRS patients with PDE9 inhibitors will result in clinically relevant improvements in blood pressure and / or blood glucose and / or insulin and / or lipids and / or uric acid and / or procoagulant factors. . Such treatment may be performed alone or in combination with other therapeutic agents that enhance IRS. Improving the clinical condition should reduce the risk of developing cardiovascular disease in the patient, and other complications of the individual disease, including but not limited to diabetic neuropathy, nephropathy and retinopathy.
[11] IRS presents many symptoms, but an important underlying epidemiological basis for disease is resistance to both the vascular and metabolic effects of insulin. In addition, the underlying pathology of vascular resistance in insulin resistance syndrome is the reduction of the amount of NO produced by endothelial cells in response to insulin. In insulin resistance patients, there is an insufficiency of insulin signaling for glucose uptake.
[12] Amplifying cGMP signals using cGMP PDE9 inhibitors in IRS patients enhances insulin glucose uptake signals and improves insulin action in key tissues. Increasing insulin sensitivity improves clinical variables of IRS outcomes, especially in the following sections:
[13] 1. Glucose Control: In patients with type 2 diabetes or impaired glucose tolerance, improving insulin sensitivity results in a decrease in plasma glucose concentrations (fasting or after oral glucose tolerance tests or meals). In a related manner as controlled by the patient's pathophysiology, there will be an improvement in fasting state, or glucose load or post-meal serum insulin concentrations. This improvement in glycemic control in patients with type 2 diabetes results in an improvement in the measure of long-term blood glucose control, such as but not limited to hemoglobin A1c (glycosylated hemoglobin) or fructosamine.
[14] 2. Blood Pressure: Improving insulin sensitivity is believed to result in improvement of both systolic and diastolic blood pressure.
[15] 3. Lipids: Improvement in insulin resistance results in improvement of serum lipids, including but not limited to serum cholesterol and triglycerides.
[16] 4. Uric acid: An improvement in insulin resistance leads to an improvement in serum uric acid.
[17] 5. Coagulation Factors: Improvement in insulin resistance is believed to restore normal factors that exacerbate procoagulant conditions.
[18] cGMP PDE9 inhibitors increase the amount of accumulated cGMP by preventing the effect of the phosphodiesterase 9 enzyme converting cGMP to inactive GMP. This accumulation amplifies the vasodilator, metabolic and anti-atherogenic effects of available nitric oxide and insulin. This amplification action alleviates the side effects associated with IRS and ameliorates one or more associated conditions.
[19] Diabetes is characterized by metabolic deficiencies in the production and use of carbohydrates, which result in increased blood sugar or hyperglycemia by failing to maintain adequate blood sugar levels. Diabetes treatment research has focused on attempts to normalize fasting and postprandial blood sugar levels. Current treatments include the administration of exogenous insulin, oral administration of drugs, diet and exercise curing.
[20] Two major forms of diabetes are recognized. Type 1 diabetes or insulin dependent diabetes is the result of an absolute deficiency of insulin, a hormone that regulates carbohydrate utilization. Type 2 diabetes or insulin-independent diabetes often occurs at normal or even elevated levels of insulin, and tissues do not respond properly to insulin. It seems to be a bad result. Complications of type 2 diabetes include retinopathy, nephropathy, neuropathy and coronary heart disease, and are believed to be facilitated by excessive protein glycation due to excessive blood sugar concentrations. Reduction of hyperglycemia by treatment with PDE inhibitors will lower protein glycosylation levels and lead to a reduction in the diabetic complications.
[21] Polycystic ovary syndrome (PCOS), also known as Stein-Leventhal syndrome or functional ovarian hyperandrogenism, causes long-term ovulation deficiency (ovulation) and excessive blood androgens (male hormones such as testosterone). Is a complex endocrine disease associated with. The disease is characterized by the formation of a cyst in the ovary, a process that is associated with the ovary not liberating the egg. In most cases, the ovary enlarges. PCOS suffers up to 22% of women during the fertile period (only 10% of them show symptoms). This is one of the most frequent causes of female infertility.
[22] Summary of the Invention
[23] The present invention relates to a method of treating IRS in a mammal comprising administering to said mammal a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. will be. In a preferred aspect of the invention, the method comprises administering a pharmaceutical composition comprising a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle, diluent or carrier.
[24] In addition, the present invention comprises administering to a mammal a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. To a method of treatment. In a preferred aspect of the invention, the method comprises administering a pharmaceutical composition comprising a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle, diluent or carrier.
[25] The present invention also provides a method of treating type 1 diabetes in a mammal comprising administering to said mammal a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. To a method of treatment. In a preferred aspect of the invention, the method comprises administering a pharmaceutical composition comprising a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle, diluent or carrier.
[26] In addition, the present invention comprises administering to a mammal a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. To a method of treatment. In a preferred aspect of the invention, the method comprises administering a pharmaceutical composition comprising a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle, diluent or carrier.
[27] The invention also relates to dyslipidemia in said mammal comprising administering to said mammal a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. And, for example, but not limited to, methods of treating hypertriglyceridemia and high LDL cholesterol. As used herein, dyslipidemia refers to a change in blood lipid profile. In a preferred aspect of the invention, the method comprises administering a pharmaceutical composition comprising a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle, diluent or carrier.
[28] In addition, the present invention comprises administering to a mammal a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. To a method of treatment. In a preferred aspect of the invention, the method comprises administering a pharmaceutical composition comprising a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug or solvate. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle, diluent or carrier.
[29] In a further aspect, the present invention provides a cGMP PDE9 inhibitor, a prodrug, solvate or salt thereof and one or more protein kinase inhibitors independently selected, a prodrug, solvate or salt thereof; AMP-activated protein kinase activators, prodrugs, solvates or salts thereof; Weight loss agents, prodrugs, solvates or salts thereof; insulin; PPAR-γ agonists, prodrugs, solvates or salts thereof; PPAR-γ antagonists, their prodrugs, solvates or salts; PPAR-α agonists, prodrugs, solvates or salts thereof; Dual PPAR-γ / PPAR-α agonists, prodrugs, solvates or salts thereof; Sorbitol dehydrogenase inhibitors, prodrugs, solvates or salts thereof; Glycogen phosphorylase inhibitors, prodrugs, solvates or salts thereof; Biguanides such as metformin, prodrugs, solvates or salts thereof; HMG-CoA reductase inhibitors, prodrugs, solvates or salts thereof; Aldose reductase inhibitors, prodrugs, solvates or salts thereof; PDE5 inhibitors, prodrugs, solvates or salts thereof; PDE11 inhibitors, prodrugs, solvates or salts thereof; Or to a first combination comprising two active ingredients selected from CETP inhibitors, prodrugs, solvates or salts thereof. Particularly preferred combinations are combinations of cGMP PDE9 inhibitors, prodrugs, solvates or salts thereof and PDE5 inhibitors, prodrugs, solvates or salts thereof. In a further aspect, the present invention relates to a pharmaceutical composition comprising said first combination and a pharmaceutically acceptable vehicle, carrier or diluent. In a further aspect, the present invention relates to a method of treating insulin resistance in a mammal comprising administering to said mammal said first formulation or pharmaceutical composition comprising said first formulation. In a further aspect, the present invention relates to a method of treating type 2 diabetes in a mammal comprising administering to the mammal said first formulation or a pharmaceutical composition comprising said first combination.
[30] In a further aspect, the invention provides a cGMP PDE9 inhibitor, a prodrug, solvate or salt thereof; cGMP PDE5 inhibitors, prodrugs, solvates or salts thereof; And three active ingredients selected from cGMP PDE11 inhibitors, prodrugs, solvates or salts thereof. In a further aspect, the present invention relates to a pharmaceutical composition comprising said second combination and a pharmaceutically acceptable vehicle, carrier or diluent. In a further aspect, the present invention relates to a method of treating insulin resistance in a mammal comprising administering to said mammal said pharmaceutical composition comprising said second formulation or said second combination. In a further aspect, the present invention relates to a method of treating type 2 diabetes in a mammal comprising administering to said mammal said pharmaceutical composition comprising said second formulation or said second combination.
[31] In addition, the present invention
[32] a) a first unit dosage form comprising a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said compound, prodrug or solvate and a pharmaceutically acceptable vehicle, carrier or diluent;
[33] b) protein kinase inhibitors; AMP-activated protein kinases; Weight loss agents; insulin; PPAR-γ agonists; PPAR-γ antagonists; PPAR-α agonists; Dual PPAR-γ / PPAR-α agonists; Sorbitol dehydrogenase inhibitors; Glycogen phosphorylase inhibitors; Biguanides such as metformin; HMG-CoA reductase inhibitors; Aldose reductase inhibitors; PDE5 inhibitors; PDE11 inhibitors; CETP inhibitors; Or the protein kinase inhibitor, AMP-activated protein kinase, weight loss agent, insulin, PPAR-γ agonist, PPAR-α agonist, dual PPAR-γ / PPAR-α agonist, sorbitol dehydrogenase inhibitor, glycogen phosphorylase inhibitor Prodrugs or solvates of biguanides, vastatin, aldose reductase inhibitors, PDE5 inhibitors, PDE11 inhibitors or CETP inhibitors; Or a second unit dosage form comprising a pharmaceutically acceptable salt of said compound, prodrug or solvate and a pharmaceutically acceptable vehicle, carrier or diluent; And
[34] c) containers
[35] It relates to a kit comprising a.
[36] In addition, the present invention
[37] a) a first unit dosage form comprising a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said compound, prodrug or solvate and a pharmaceutically acceptable vehicle, carrier or diluent;
[38] b) a second unit dosage form comprising a cGMP PDE5 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said compound, prodrug or solvate and a pharmaceutically acceptable vehicle, carrier or diluent;
[39] c) a third unit dosage form comprising a cGMP PDE11 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said compound, prodrug or solvate and a pharmaceutically acceptable vehicle, carrier or diluent; And
[40] c) containers
[41] It relates to a kit comprising a.
[42] A further aspect of the present invention provides a method of treating IRS as defined above in a mammal comprising administering to the multiple insulin resistant mammal an effective amount of a cGMP PDE9 inhibitor or a pharmaceutical composition thereof. A further aspect of the present invention provides a method of treating said polygenic insulin resistant mammal with a combination of a cGMP PDE9 inhibitor and a second compound as defined above, or a pharmaceutical composition comprising said combination and a pharmaceutically acceptable vehicle, carrier or diluent. will be. Another aspect of the present invention is the treatment of the multiple insulin resistant mammal with the kit described above.
[43] The suitability of any particular cGMP PDE9 inhibitor can be readily determined by selectively evaluating its efficacy using literature methods and then evaluating its toxicity, absorption, metabolism, pharmacokinetics and the like according to general pharmaceutical criteria.
[44] Preferably, the cGMP PDE9 inhibitor exhibits an IC ₅₀ at less than 100 nM, more preferably less than 50 nM, even more preferably less than 15 nM.
[45] IC ₅₀ values of cGMP PDE9 inhibitors can be determined using the PDE9 assay in the Test Methods section below.
[46] It is to be understood that the content of the published patent applications, in particular the general formulas and the compounds exemplified therein, are hereby incorporated by reference in their entirety.
[47] Preferred groups of cGMP PDE9 inhibitors for use in the methods, compositions, combinations and kits of the invention include compounds of formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof:
[48]
[49] Where
[50] R ¹ is H or (C ₁ -C ₆ ) alkyl;
[51] R ² is straight or branched chain (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl or heteroaryl;
[52] R ³ is substituted by 1 to 2 groups independently selected from Ar, (C ₃ -C ₇ ) cycloalkyl, OAr, SAr, NC (O) (C ₁ -C ₆ ) alkyl, heteroaryl, xanthene and naphthalene Linear or branched (C ₁ -C ₆ ) alkyl which may be;
[53] Ar is a group of the formula:
[54]
[55] Wherein R ⁴ , R ⁵ and R ⁶ are H, halo, phenoxy, phenyl, CF ₃ , OCF ₃ , S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, O (C Independently selected from ₁ -C ₆ ) alkyl, said alkyl may be substituted by 1 to 3 groups selected from a heteroaryl group or a phenyl group (phenyl group is selected from halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl Or R ⁴ and R ⁵ together may form a (C ₂ -C ₃ ) alkyl linking group which may comprise a heteroatom selected from O, S and N)
[56] Heteroaryl is a 5-6 membered aromatic heterocycle containing 1-3 heteroatoms independently selected from O, S and N, said heterocycle being (C ₁ -C ₆ ) alkyl, halo and phenyl (phenyl May be substituted by 1 to 3 substituents independently selected from halo and 1 to 3 groups selected from (C ₁ -C ₆ ) alkyl; Provided that when R ¹ is -CH ₃ , R ² cannot be -CH ₂ CH ₂ CH ₃ .
[57] Particularly preferred groups of compounds in the preferred group are those wherein R ¹ is H or CH ₃ . More preferably, R ¹ is H.
[58] Another particularly preferred group of compounds in a preferred group is a compound in which R ² is selected from (C ₃ -C ₄ ) alkyl, cyclopentyl and pyridinyl. More preferably, R ² is 3-pyridinyl.
[59] Another particularly preferred group of compounds in the preferred groups are those wherein R ³ is (C ₁ -C ₃ ) alkyl which may be substituted by 1 to 2 groups selected from Ar, (C ₃ -C ₇ ) cycloalkyl and heteroaryl to be. More preferably, R ³ is C ₁ alkyl substituted by Ar wherein R ⁴ , R ⁵ and R ⁶ are H.
[60] Another particularly preferred group of compounds in the preferred groups include those in which R ⁴ , R ⁵ and R ⁶ are H, halo, phenoxy, phenyl, CF ₃ , OCF ₃ , S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, O (C ₁ -C ₆ ) alkyl independently selected from alkyl, heteroalkyl group or phenyl group (phenyl group is selected from halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl 1 to May be substituted by three groups); R ⁴ and R ⁵ together are a compound capable of forming a C ₂ alkyl linking group containing an O atom. More preferably, R ⁴ , R ⁵ and R ⁶ are independently selected from H, halo, OCF ₃ , CF ₃ , OAr and O (C ₁ -C ₆ ) alkyl, wherein said alkyl is a heteroaryl group or a phenyl group ( The phenyl group may be substituted by H, halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl). Even more preferably, R ⁴ , R ⁵ and R ⁶ are independently selected from Cl, H, OCF ₃ , CF ₃ , and O (C ₁ -C ₆ ) alkyl substituted by phenyl. Most preferably, R ⁴ , R ⁵ and R ⁶ are independently selected from O (C ₁ -C ₃ ) alkyl substituted by H, Cl, and phenyl.
[61] Another particularly preferred group of compounds in the preferred group is a 5-6 membered aromatic heterocycle wherein heteroaryl contains two or more N atoms, wherein the heterocycle is independently from (C ₁ -C ₆ ) alkyl, halo and phenyl It may be substituted by 1 to 3 substituents selected and the phenyl may be substituted by 1 to 3 groups selected from halo and (C ₁ -C ₆ ) alkyl. More preferably, heteroaryl is a 5 membered aromatic heterocycle containing two or more N atoms, said heterocycle may be substituted by one substituent selected from (C ₁ -C ₆ ) alkyl, halo and phenyl , Wherein the phenyl may be substituted by one to three groups selected from halo and (C ₁ -C ₆ ) alkyl. Even more preferably, heteroaryl is a 5 membered aromatic heterocycle containing two or more N atoms, which heterocycle may be substituted by phenyl which may be substituted by halo. Most preferably, heteroaryl is imidazole or oxadiazole.
[62] Particularly preferred cGMP PDE9 inhibitors are 5- (3-chloro-benzyl) -3-isopropyl-1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one, a prodrug thereof, or the above Pharmaceutically acceptable salts of compounds or prodrugs.
[63] According to a further aspect, the present invention provides insulin resistance in patients with type 2 diabetes or impaired glucose tolerance or in patients with dyslipidemia, hypertension, hyperuricemia, procoagulant, atherosclerosis or central obesity, and a family history of diabetes. The use of a PDE9 inhibitor or a pharmaceutical composition thereof for the treatment of the syndrome is provided.
[64] According to a further aspect, the present invention requires administering to a mammal a PDE9 inhibitor, a prodrug thereof, a pharmaceutically acceptable salt of the PDE9 inhibitor or a prodrug, or a pharmaceutical composition comprising a PDE9 inhibitor. A mammal is provided with a method of increasing intracellular cGMP. For this reason, it is particularly preferable to treat type 2 diabetes, insulin resistance syndrome or high blood pressure.
[65] According to a further aspect, the present invention provides a method of treating high blood pressure in a mammal comprising administering to the mammal a PDE9 inhibitor, a prodrug thereof, or a pharmaceutically acceptable salt of the PDE9 inhibitor or prodrug. do. The PDE9 inhibitor is 5- (3-chloro-benzyl) -3-isopropyl-1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one, a prodrug thereof, or the compound or Particularly preferred is a pharmaceutically acceptable salt of the prodrug.
[1] The present invention relates to the use of cGMP PDE9 inhibitors for the treatment of type 2 diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, type 1 diabetes and / or insulin resistance syndrome (IRS). The present invention also relates to combinations comprising cGMP PDE9 inhibitors and other agents useful for the treatment of type 2 diabetes, hyperglycemia, dyslipidemia, dyslipidemia, type 1 diabetes and / or insulin resistance syndrome.
[66] PDE9 inhibitors for use in the pharmaceutical compositions and methods of the present invention may be prepared as set forth in the Examples below, or may be prepared according to methods analogous to those set forth in US Pat. No. 6,235,742, which is incorporated herein by reference.
[67] Pharmaceutically acceptable salts of the cGMP PDE9 inhibitors disclosed herein for use in the treatment of insulin resistance syndrome according to the invention containing a basic center are, for example, hydrochloric acid, bromic acid, iodic acid, sulfuric acid and phosphoric acid; And non-toxic acid addition salts formed with the same inorganic acid, carboxylic acid or organo-sulfonic acid. Examples include HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharide, fumarate, maleate, lactate, citrate, tartrate, Gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. CGMP PDE9 inhibitor compounds for use in the present invention may also provide pharmaceutically acceptable metal salts with bases, in particular non-toxic alkali and alkaline earth metal salts. Examples include sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts. For a review of suitable pharmaceutical salts, see Berge et al, J. Pharm. Sci., 66, 1-19, 1977.
[68] CGMP PDE9 inhibitor compounds suitable for use in accordance with the present invention, pharmaceutically acceptable salts thereof, and both pharmaceutically acceptable solvates may be administered alone, but in human therapy generally the desired route of administration And appropriate pharmaceutical excipients, diluents or carriers selected in connection with the general pharmaceutical criteria.
[69] For example, a cGMP PDE9 inhibitor compound or salt or solvate thereof suitable for use in accordance with the present invention will contain tablets, capsules (including soft capsules), multi-granules, gels, films, turbulences, elixirs, flavors or colorants. Oral, buccal or sublingual administration for immediate-, delayed-, modified-, sustained-release, dual-, controlled-release or pulse delivery applications in the form of a viable solution or suspension. In addition, the compounds may be administered in a rapid dispersion or rapid dissolution dosage form, or in the form of high energy dispersions or coated particles. Suitable formulations may be in coated or uncoated form as needed.
[70] Such solid pharmaceutical compositions, e.g. tablets, may contain microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, excipients such as glycine and starch (preferably corn, potato or tapioca starch), sodium starch glycol Disintegrants such as latex, croscarmellose sodium and certain complex silicates, and polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS) And granulating binders such as sucrose, gelatin and gum arabic. Additionally, glidants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
[71] Solid compositions of a similar type may also be used as fillers in gelatin capsules or HPMC capsules. Preferred excipients in this respect include lactose, starch, cellulose, lactose or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, cGMP PDE9 inhibitor compounds are mixed with various sweeteners or flavors, colorants or dyes, emulsifiers and / or suspending agents and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof Can be.
[72] Modified release and pulsed release dosage forms may contain additional excipients that act as rate controlling agents coated on and / or contained within the body of the device, together with excipients such as those described above for immediate release dosage forms. . Release rate modifiers include HPMC, HPMCAS, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba beeswax, paraffin Lead, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymers, and mixtures thereof. Modified release and pulsed release dosage forms may contain one release rate controlling excipient or a combination thereof. Release rate controlling excipients may be present within a dosage form, ie, within a matrix and / or on a dosage form, ie, on a surface or a coating.
[73] Rapid disperse or dissolution dosage compositions (FDDFs) include aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate , Mannitol, methyl methacrylate, peppermint, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The term dispersion or dissolution, as used herein to describe FDDFs, depends on the solubility of the drug used. That is, if the drug is insoluble, a quick disperse dosage form can be prepared, and if the drug is soluble, a quick dissolve dosage form can be prepared.
[74] Suitable cGMP PDE9 inhibitor compounds for use according to the invention are also parenterally, e.g., intracavernous, intravenous, intraarterial, intraperitoneal, intradural, intraventricular, urethra, intrasternal, intracranial, muscle It may be administered intra or subcutaneously, or may be by infusion or needle-free techniques. In the case of parenteral administration, the compounds are best used in the form of sterile aqueous solutions which may contain enough salt or other substances such as glucose to make the solution isotonic with the blood. The aqueous solution should be buffered appropriately (preferably to a pH of 3-9) as needed. The preparation of suitable parenteral compositions under sterile conditions is readily accomplished by general pharmaceutical techniques well known to those skilled in the art.
[75] For oral and parenteral administration to human patients, the daily dose of the cGMP PDE9 inhibitor compound, or salt or solvate thereof, for use in the present invention will usually be from 1 to 500 mg (in single or divided doses). Preferred dosage ranges are from about 1 mg to about 100 mg. For IRS treatment, the dosage is continuous (chronic) for a specific period of time, which may be a single dose, divided daily doses, multiple daily doses, 1 day to 5 days or more than 5 days (eg 10 days or more). By daily administration. Alternatively, IRS treatment may be effected by sustained release, eg, a sustained release composition, where the continuous dosage form may be administered daily for several days, or when continuous administration is taken for more than one day at a time. May be affected by a controlled release dosage form.
[76] Thus, for example, a cGMP PDE9 inhibitor compound tablet or capsule suitable for use in accordance with the present invention may contain from 1 mg to 250 mg of active compound for one or two or more administrations at a time as needed. . Preferred tablets or capsules will contain from about 1 mg to about 50 mg of active compound for one or two or more administrations at a time as needed. In any case, the physician will determine the actual dose best suited for any individual patient, which will depend on the age, weight and response of the particular patient. The dose is an example of a normal case. Of course, there may be cases where a higher or lower dose range is advantageous and it is within the scope of the present invention.
[77] Suitable cGMP PDE9 inhibitor compounds for use in accordance with the present invention may also be administered intranasally or inhaled, and suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoro Alkanes (e.g., 1,1,1,2-tetrafluoroethane (HFA 134A® or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA®)), carbon dioxide Or in the form of a dry powder inhaler or aerosol spray provided from a pressurized vessel, pump, spray or nebulizer using another suitable gas, in the case of a pressurized aerosol, the dosage unit provides a valve for delivering a metered amount. Pressurized vessels, pumps, sprays or nebulizers may be, for example, mixtures of ethanol and propellant which may additionally contain a lubricant such as sorbitan trioleate. It may contain a solution or suspension of the active compound for use as a solvent Capsules and medicines (for example made of gelatin) for use in inhalers or pulverizers are suitable powders such as the compounds of the invention and lactose or starch. It may be formulated to contain a powder mixture of the substrate.
[78] The aerosol or dry powder composition is preferably such that each metered dose or "puff" contains 1 to 50 mg of a compound of the invention for delivery to a patient. The total daily dose of aerosol will range from 1 to 50 mg, which will be administered in a single dose or, more generally, in divided doses for the day.
[79] Suitable cGMP PDE9 inhibitor compounds for use in accordance with the present invention may also be formulated for delivery via a nebulizer. The nebulizer composition may contain water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycol, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid as solubilizers, emulsifiers or suspending agents.
[80] Alternatively, a cGMP PDE9 inhibitor compound, or salt or solvate thereof, suitable for use in accordance with the present invention may be administered in the form of suppositories or vaginal suppositories, or gels, hydrogels, lotions, solutions, creams, ointments or powdered powders. Topical administration in the form. Suitable cGMP PDE9 inhibitor compounds, or salts or solvates thereof, for use in accordance with the present invention may also be administered dermal or transdermal using, for example, skin patches. They can also be administered by the pulmonary or rectal route.
[81] The compound may also be administered by the ocular route. For ophthalmic use, the compounds may be formulated with a preservative such as benzylalkonium chloride, in an undifferentiated suspension in isotonic, pH adjusted sterile saline, or preferably in a solution in isotonic, pH adjusted sterile saline. Alternatively, they may be formulated in an ointment such as petrolatum.
[82] For topical administration to the skin, suitable cGMP PDE9 inhibitor compounds, or salts or solvates thereof, for use in accordance with the present invention are, for example, mineral oil, liquefied petroleum, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene It may be formulated into a suitable ointment containing the active compound suspended or dissolved in a mixture with one or more of the compound, emulsifying wax and water. Alternatively, they can be, for example, one of mineral oil, sorbitan monostearate, polyethylene glycol, liquefied paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water It may be formulated into a suitable lotion or cream suspended or dissolved in the above mixture.
[83] Suitable cGMP PDE9 inhibitor compounds for use in accordance with the invention may also be used with cyclodextrins. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of the drug-dextrin complex will alter the solubility, dissolution rate, bioavailability and / or stability of the drug molecule. Drug-dextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug, cyclodextrin may be used as an auxiliary additive such as a carrier, diluent or solubilizer. Alpha-, beta- and gamma-dextrins are most commonly used and suitable examples are described in WO 91/11171, WO 94/02518 and WO 98/55148.
[84] In general, in humans, oral administration is the preferred route and most convenient. If the recipient suffers from swallowing disorders or poor drug absorption after oral administration, the drug can be administered parenterally, sublingually or orally.
[85] For veterinary use, the compound, or veterinary acceptable salt, veterinary acceptable solvate or prodrug thereof, is administered in a suitably acceptable composition in accordance with general veterinary criteria and the veterinarian is most suitable for a particular animal. Dosage regimen and route of administration will be determined.
[86] Treatment herein includes healing, palliative and prophylactic treatment.
[87] The invention further encompasses the use of a combination of first and second compounds for the treatment of insulin resistance syndrome or type 2 diabetes. The first compound of the combination is a cGMP PDE9 inhibitor as defined herein. The second compound of the combination may be natural or synthetic prostaglandins or esters thereof; α-adrenergic receptor antagonist compounds (also known as α-adrenoceptors, α-receptors or α-blockers); Nitric oxide donors (also known as NO-donors or NO-agents); Potassium channel initiator or potassium channel regulator; Dopamine-like drugs; Vasodilators; Thromboxane A2 agonists; Ergot alkaloids; Compounds that modulate the action of a naturalistic factor, in particular compounds that modulate the action of atrial naturtic factor (also known as atrial naturtic peptide), type B and C naturalistic factor; Angiotensin receptor antagonists; Substrates for NO-synthase; Calcium channel blockers; Endothelin receptor antagonists; Endothelin converting enzyme inhibitors; Cholesterol lowering agents such as HMG-CoA reductase inhibitors; Antiplatelet or antithrombotic agents; Insulin sensitizers such as glitazones; Insulin secretagogues such as sulfonylureas; Acetylcholinesterase inhibitors; Estrogen receptor modulators; PDE5 inhibitors; PDE11 inhibitors; Neuropeptide Y (NPY) inhibitors, preferably NPY5 inhibitors, more preferably NPY1 inhibitors (the NPY inhibitors exhibit an IC ₅₀ of less than 100 nM, more preferably less than 50 nM); Angiogenic enteropeptide (VIP) or VIP analogs, in particular VIP mediated by one or more of the VIP receptor subtype VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide); VIP receptor antagonists; VIP analogs or fragments; α-adrenoceptor antagonist / VIP combinations (eg, Invicorp®, Aviptadil); Serotonin receptor agonists, antagonists or modulators, particularly 5HT1A modulators; Testosterone replacement drugs; Estrogens; Combinations of estrogen and hydroxyprogesterone; Combinations of estrogen and hydroxyprogesterone acetate (MPA); Combinations of estrogen and methyl testosterone hormone replacement therapy (eg, HRT); Noradrenaline, dopamine or serotonin transporter modulators; Purine receptor agonists or modulators; Neurokinin (NK) receptor antagonists; Opiate receptor agonists, antagonists or modulators, preferably ORL-1 receptor agonists; Oxytocin / vasopressin receptor modulators or agonists, preferably selective oxytocin agonists or modulators; Cannabinoid receptor modulators; Central nervous system (CNS) activators; Angiotensin converting enzyme inhibitors; Combinations of angiotensin converting enzyme inhibitors and neutral endopeptidase; L-dopa; Combinations of L-dopa and carbidopa; Steroidal anti-inflammatory agents; Non-steroidal anti-inflammatory agents; Protein kinase C-β inhibitors; AMP-activated protein kinase activator; insulin; Weight loss agents; Dipeptidyl peptidase IV (DPP IV) inhibitors; Glucagon antagonists; I kappa B kinase-β (IKK-β) inhibitors such as salicylates; PTP1B inhibitors; Agents that reduce PTP1B levels using antisense technology; Glycogen synthase kinase-3 inhibitors; GLP-1 agonists; PPAR-γ agonists; PPAR-γ antagonists; PPAR-α agonists; Dual PPAR-α / PPAR-γ agonists; RXR antagonists; Biguanides such as metformin; Glycogen phosphorylase inhibitors; Sorbitol dehydrogenase inhibitors (SDI); Aldose reductase inhibitor (ARI); Soluble guanylate cyclase (sGC) activators; Growth hormone; Or growth hormone secretagogues.
[88] Natural or synthetic prostaglandins or esters thereof can be used as the second compound of the combination of the present invention. Prostaglandins suitable for use in the present invention include alprostadil, prostaglandin E ₁ , prostaglandin E ₀ , 13,14-dihydroprostaglandin E ₁ , prostaglandin E ₂ , including those described in WO 00/33825 and US Pat. No. 6,037,346. , Eprostinol, natural, synthetic and semisynthetic prostaglandins and derivatives thereof; _{PGE 0, PGE 1, PGA 1} , PGB 1, PGF 1 α, 19- hydroxy -PGA _1, 19- hydroxy _{-PGB 1, PGE 2, PGB 2} , 19- hydroxy -PGA _2, 19- hydroxy -PGB ₂ , PGE ₃ α, carboprost tromethamine dinoprost, tromethamine, dinoprostone, lipoprost, gemeprost, methenoprost, sulfprostun, thiaprost and moxisylate.
[89] The disclosures of US patents, international patent applications, and all other references mentioned herein are incorporated herein by reference.
[90] α-adrenergic receptor antagonist compounds can be used as the second compound of the combination of the present invention. Suitable α-adrenergic receptor antagonists for use in the present invention include α-adrenergic receptor blockers described in WO 99/30697. In addition, selective α ₁ - can be used as acceptor Adreno-blockers and non-selective blockers Adreno acceptor to claim 2 α- adrenergic receptor antagonist compounds of the invention - Adreno acceptor, α _2. Suitable α ₁ -adrenoceptor blockers include phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramine, naphtopidyl, tamsulosin, dapiprazole, phenoxybenzamine, idazoic acid, efalacic acid, yohimbine , Raulfa alkaloids, recordat 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin, terrazosin, abanoquil and prazosin. Suitable α ₂ -adrenoceptor blockers include those described in US Pat. No. 6,037,346, dibenanine, tolazoline, and trimazocin. In addition, α-adrenergic receptor antagonists suitable for use as the second compound of the combination of the present invention are described in US Pat. No. 4,188,390; 4,026,894; 3,511,836; 3,511,836; No. 4,315,007; 3,527,761; 3,997,666; 2,503,059; 2,503,059; No. 4,703,063; 3,381,009; 4,252,721; And 2,599,000. Other suitable α ₂ -adrenoceptor blockers include clonidine, papaverine, papaverine hydrochloride, each of which may be administered in the presence of a carriotonic agent such as pyramine.
[91] Nitric oxide donor (NO-donor or NO-agent) compounds may be used as the second compound of the combination of the present invention. Suitable NO-donor compounds for use in the present invention include organic nitrates such as mono-, di- or tri-nitrate; Glyceryl binitrate (also known as nitroglycerin), isosorbide 5-monitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythritol tetranitrate, amylnitrate, diazenium Organic nitrate esters such as NONOate and 1,5-pentanedinitrate; Sodium nitroprusside (SNP); 3-morpholinosidenonimine molsididomine; S-nitroso-N-acetyl penicylamine (SNAP); S-nitroso-N-glutathione (SNO-GLU); N-hydroxy-L-arginine; Lincidomin; Lincidomin chlorohydrate; (SIN-1) S-nitroso-N-cysteine; L-arginine; Ginseng; Jizzpie fructus; Molecidomin; Re-2047; And nitrosylated maxyllite derivatives (WO 00/12075) such as NMI-678-11 and NMI-937.
[92] Any potassium channel initiator or modulator can be used as the second compound of the combination of the present invention. Potassium channel initiators / modulators suitable for use in the present invention include nicolandil, chromocalim, revchromacalim, remacalim, finacyldyl, cliaxoxide, minoxidil, caribdotoxin, glyburide, glipizide , 4-amiminipyridine and barium chloride (BaCl ₂ ).
[93] Dopamine-like drugs can be used as the second compound of the combination of the present invention. Preferred dopamine-like drugs are apomorphine and selective D2, D3 and D2 / D3 agonists such as pramipexole, ropylinol (WO 00/23056), L-dopa, a combination of carbidopa and L-dopa, PNU95666 (WO 00/40226).
[94] Any vasodilator may be used as the second compound of the combination of the present invention. Vasodilation agents suitable for use in the present invention include nimodepine, pinassidyl, cyclandelite, isoxuprine, chloroprazine, haloperidol, Rec 15/2739 and trazodone.
[95] Any ergot alkaloid can be used as the second compound of the combination of the present invention. Suitable ergot alkaloids are those described in US Pat. No. 6,037,346; Acetergamine, Brassergoline, Bromeguride, Cyanergoline, Dellorgotril, Disulergin, Ergonobin maleate, Ergotamine tartarate, Etisulergin, Lergotryl, Risergid, Mesureler Long, metergoline, mettergotamine, nisergoline, pergolide, propiregird, proterguride, terguride.
[96] Any angiotensin receptor antagonist can be used as the second compound of the combination of the present invention. Suitable angiotensin receptor antagonists include losartan, candersartan, eprosartan, irbesartan and valsartan.
[97] Any NO-synthase substrate can be used as the second compound of the combination of the present invention. Suitable NO-synthase substrates include, in particular, L-arginine.
[98] Any calcium channel blocker can be used as the second compound of the combination of the present invention. Suitable calcium channel blockers include amlodipine (amlodipine besylate is also known as Norvasc®); Befridil (may be prepared as described in US Pat. No. 3,962,238 or US Reissue Pat. No. 30,577); Clentiazem (which may be prepared as described in US Patent No. 4,567, 175); Diltiazem (which may be prepared as described in US Patent No. 3,562); Pendylin (may be prepared as described in US Pat. No. 3,262,977); Galopamil (may be prepared as described in US Pat. No. 3,261,859); Mibepradil (may be prepared as described in US Pat. No. 4,808,605); Prenylamine (may be prepared as described in US Pat. No. 3,152,173); Semotiadil (may be prepared as described in US Pat. No. 4,786,635); Terodidyline (which may be prepared as described in US Patent No. 3,371,014); Verapamil (may be prepared as described in US Pat. No. 3,261,859); Aranipine (may be prepared as described in US Pat. No. 4,572,909); Barnidipine (may be prepared as described in US Pat. No. 4,220,649); Benidipine (which may be prepared as described in European Patent Application Publication No. 106,275); Silnidipine (may be prepared as described in US Pat. No. 4,672,068); Eponifidine (may be prepared as described in US Pat. No. 4,885,284); Elgodipine (may be prepared as described in US Pat. No. 4,952,592); Felodipine (may be prepared as described in US Pat. No. 4,264,611); Isradipine (may be prepared as described in US Pat. No. 4,466,972); Lacidipine (may be prepared as described in US Pat. No. 4,801,599); Lercanidipine (may be prepared as described in US Pat. No. 4,705,797); Manidipine (may be prepared as described in US Pat. No. 4,892,875); Nicardipine (may be prepared as described in US Pat. No. 3,985,758); Nifedipine (may be prepared as described in US Pat. No. 3,485,847); Nilvadipine (which may be prepared as described in US Patent No. 4,338,322); Nimodipine (can be prepared as described in US Pat. No. 3,799,934); Nisoldipine (may be prepared as described in US Pat. No. 4,154,839); Nitrendipine (may be prepared as described in US Pat. No. 3,799,934); Cinnarizine (which may be prepared as described in US Patent No. 2,882,271); Flunarizine (which may be prepared as described in US Patent No. 3,773,939); Lidofrazine (may be prepared as described in US Pat. No. 3,267,104); Lomerizin (may be prepared as described in US Pat. No. 4,663,325); Bencyclane (which may be prepared as described in Hungarian Patent No. 151,865); Etaphenone (may be prepared as described in German Patent No. 1,265,758); And perhexylline (which may be prepared as described in British Patent No. 1,025,578).
[99] Any cholesterol lowering agent can be used as the second compound of the combination of the present invention. Suitable cholesterol lowering agents include simvastatin, disclosed in US Pat. No. 4,444,784; Pravastatin, disclosed in US Pat. No. 4,346,227; Cerivastatin disclosed in US Pat. No. 5,502,199; Mevastatin, disclosed in US Pat. No. 3,938,140; Belostatin disclosed in U.S. Patent 4,448,784 and U.S. Patent 4,450,171; Fluvastatin, disclosed in US Pat. No. 4,739,073; Compactin, disclosed in US Pat. No. 4,804,770; Lovastatin, disclosed in US Pat. No. 4,231,938; Dalvastatin, disclosed in European Patent Application Publication No. 738,510 A2; Fluindostatin, disclosed in European Patent Application Publication No. 363,934 A1; Atorvastatin, disclosed in US Pat. No. 4,681,893; Atorvastatin calcium (also known as Lipitor®) disclosed in US Pat. No. 5,273,995; And vastatin, such as dihydrocompactin disclosed in US Pat. No. 4,450,171. Other suitable cholesterol lowering agents include fibrate.
[100] Any antiplatelet and antithrombotic agent can be used as the second compound of the combination of the present invention. Suitable antiplatelet and antithrombotic agents include, for example, tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin and thromboplastin activator inhibitors.
[101] Any insulin sensitizer can be used as the second compound of the combination of the present invention. Suitable insulin sensitizers include hypoglycemic agents such as Avandia®, Actos® and sulfonylureas (e.g., glipizide, metformin and acarbose).
[102] Any acetylcholinesterase inhibitor can be used as the second compound of the combination of the present invention. Suitable acetylcholinesterase inhibitors are, for example, donegiefil.
[103] Any estrogen receptor modulator, estrogen agonist or estrogen antagonist can be used as the second compound of the combination of the present invention. Suitable estrogen receptor modulators, estrogen agonists or estrogen antagonists include the compounds described in WO 96/21656 and US Pat. No. 5,552,412. Preferred compounds are raloxyphene, lasopoxifen, (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7, 8-tetrahydronaphthalen-2-ol and its pharmaceutically acceptable salts.
[104] Any PDE5 or PDE11 inhibitor can be used as the second compound of the combination of the present invention. Particular preference is given to using PDE5 inhibitors as second compounds of the invention. Suitable PDE5 inhibitors include pyrazolo [4,3-d] pyrimidin-7-ones disclosed in EP-A-0463756; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in EP-A-0526004; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 93/06104; Pyrazolo [3,4-d] pyrimidin-4-ones disclosed in WO 93/07149; Quinazolin-4-ones disclosed in WO 93/12095; Pyrido [3,2-d] pyrimidin-4-ones disclosed in WO 94/05661; Purin-6-ones disclosed in WO 94/00453; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 98/49166; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 99/54333; Pyrazolo [4,3-d] pyrimidin-4-ones disclosed in EP-A-0995751; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 00/24745; Pyrazolo [4,3-d] pyrimidin-4-ones disclosed in EP-A-0995750; The compounds disclosed in WO 95/19978; The compounds disclosed in WO 99/24433; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 01/27112; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 01/27113; The compounds disclosed in EP-A-1092718; The compounds disclosed in EP-A-1092719; The compounds disclosed in WO 93/07124.
[105] Preferred PDE5 inhibitors for use as the second compound of the combination of the present invention are 1-[[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3 -d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methylpiperazine also known as 5- [2-ethoxy-5- (4-methyl-1-piperazinyl Sulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil) (EP-A-0463756 see ); 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- On (see EP-A-0526004); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H -Pyrazolo [4,3-d] pyrimidin-7-one (see WO 98/49166); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl- 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 99/54333); 6-benzo [1,3] dioxol-5-yl-2-methyl-2,3,6,7,12,12a-hexahydro-pyrazino [1 ', 2': 1,6] pyrido [ 3,4-b] indole-1,4-dione (cialis); 3-ethyl-5- {5- [4-ethylpiperazin-1-ylsulfonyl] -2-([(1R) -2-methoxy-1-methylethyl] oxy) pyridin-3-yl} -2 (+)-3-ethyl-5- [5- (4-ethylpiperazine, also known as -methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one -1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one (see WO 99/54333); 1- {6-Ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-d] pyrimidine- 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-also known as 5-yl] -3-pyridylsulfonyl) -4-ethylpiperazine 3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (W0 01/27113, see Example 8); 5- [2-iso-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1-methylpiperidin-4-yl)- 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (W0 01/27113, see Example 15); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one (W0 01/27113, see Example 66); 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one (W0 01/27112, see Example 124); 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one (W0 01/27112, see Example 132); (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6,1 ] Pyrido [3,4-b] indole-1,4-dione (IC-351), ie the compounds of Examples 78 and 95 of WO 95/19978, and the compounds of Examples 1,3, 7 and 8 ; 1-[[3- (3,4-Dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-f] -as-triazin-2-yl) -4-ethoxy 2- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-, also known as phenyl] sulfonyl] -4-ethylpiperazine 7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one (vardenafil), ie Examples 20, 19, 337 and 336 of WO 99/24433 Compound of; The compound of Example 11 of WO 93/07124 (EISAI); And in Rotella DP, J. Med. Chem. , 2000, 43, 1257].
[106] Another cGMP PDE5 inhibitor useful in the present invention includes 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) -propoxy] -3 (2H) pyridazinone; 1- [4-[(1,3-benzodioxol-5-ylmethyl) amiono] -6-chloro-2-quinozolinyl] -4-piperidine-carboxylic acid, 1 sodium salt; (+)-Cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) -phenylmethyl-5-methyl-cyclopent-4,5] imidazo [ 2,1-b] purin-4 (3H) one; Furazlocillin; Cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] -imidazo [2,1-b] purin-4-one ; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3 (2H) pyridazinone; 1-methyl-5 (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidine-7 -On; 1- [4-[(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid, 1 sodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharma Project No. 5051 (Bayer); Pharma Project 5064 (Kyowa Hakko; see WO 96/26940); Pharma Project No. 5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer) and Sch-51866; Sildenafil; 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- On; 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H -Pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl- 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (2-methoxyethyl) -2,6-dihydro- 7H-pyrazolo [4,3-d] pyrimidin-7-one; And 1-[[3- (3,4-dihydro-5-methyl-4-oxo-7-propylimidazolo [5,1-f] -as-trizin-2-yl) -4- Methoxyphenyl] sulfonyl] -4-ethylpiperazine, or a pharmaceutically acceptable salt, solvate, prodrug or polymorph thereof.
[107] More preferred cGMP PDE5 inhibitors for use as the second compound in the formulations of the present invention are sildenafil, sildenafil citrate (also known as Viagra®; 5- (5-acetyl-2-butoxy-3-pyridinyl) 3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; in 2- [2- Toxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4 ] Triazin-4-one (vardenafil); 6-benzo [1,3] dioxol-5-yl-2-methyl-2,3,6,7,12,12a-hexahydro-pyrazino [ 1 ', 2': 1,6] pyrido [3,4-b] indole-1,4-dione (cialis); and 5- [2-ethoxy-5- (4-ethylpiperazin-1- Monosulfonyl) pyridin-3-yl] -3-ethyl-1- (2-methoxyethyl) -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one do.
[108] Any melanocortin receptor agonist, melanocortin receptor modulator or melanocortin receptor enhancer can be used as the second compound of the combination of the present invention. Suitable melanocortin receptor agonists, modulators or enhancers include melanotan II; PT-14; PT-141; And the compounds disclosed in WO 99/64002, WO 00/74679, WO 99/55679, WO 01/05401, WO 00/58361, W001 / 14879, WO 01/13112, and WO 99/54358.
[109] Any serotonin receptor agonist, antagonist or modulator can be used as the second compound of the combination of the present invention. Particular preference is given to using agents, antagonists or modulators of 5HT1A. Suitable agents, antagonists or modulators include VML 670, including those described in WO 99/02159, WO 00/02550 and WO 00/28993; 5HT2A; 5HT2C; 5HT3; And 5HT6 receptors.
[110] Any testosterone replacement may be used as the second compound in the combination of the present invention. Suitable testosterone replacements include dehydroandrostenedione, testosterone (tostrel), dihydrotestosterone and testosterone inserts.
[111] Any hormone replacement therapy (HRT) agent can be used as the second compound of the combination of the present invention. Suitable HRT medications include premarin®, cestine®, estrofeminal®, equin®, estrace®, estrofe®, elrest Solo (registered trademark), Estling (registered trademark), Estradam TTS (registered trademark), Estradem matrix (registered trademark), The Mestril (registered trademark), Premface (registered trademark), Preempro (registered trademark) ), Prempark (registered trademark), Premike (registered trademark), Estratest (registered trademark), Estratest HS (registered trademark) and Livial (registered trademark; Tibolone).
[112] Any noradrenaline, dopamine and / or serotonin transporter modulator can be used as the second compound of the combination of the present invention. Suitable regulators include bupropion and GW-320659.
[113] Any neurokinin (NK) receptor antagonist can be used as the second compound of the combination of the present invention. Suitable NK receptor antagonists include those described in WO 99/64008.
[114] Any angiotensin converting enzyme inhibitor (ACE inhibitor) can be used as the second compound of the combination of the present invention. Suitable ACE inhibitors are alacepril (which may be prepared as described in US Pat. No. 4,248,883); Benazepril (which may be prepared as described in US Patent No. 4,410,520); Captopril (may be prepared as described in US Pat. Nos. 4,046,889 and 4,105,776); Seronapril (may be prepared as described in US Pat. No. 4,452,790); Delapril (which may be prepared as described in US Patent No. 4,385,051); Enalapril (may be prepared as described in US Pat. No. 4,374,829); Posinopril (may be prepared as described in US Pat. No. 4,337,201); Imadapril (may be prepared as described in US Pat. No. 4,508,727); Lisinopril (may be prepared as described in US Pat. No. 4,555,502); Moveltopril (may be prepared as described in US Pat. No. 893,553); Perindopril (which may be prepared as described in US Patent No. 4,508, 729); Quinapril (may be prepared as described in US Pat. No. 4,344,949); Ramipril (may be prepared as described in US Pat. No. 4,587,258); Spirapril (may be prepared as described in US Pat. No. 4,470,972); Temocapryl (may be prepared as described in US Pat. No. 4,699,905); And trandolapril (which may be prepared as described in US Pat. No. 4,933,361).
[115] Any compound that is a combination inhibitor of angiotensin converting enzyme and neutral endopeptidase can be used as the second compound of the combination of the present invention. Suitable combination inhibitors are, for example, omapartrylat.
[116] Any protein kinase C-β inhibitor can be used as the second compound of the combination of the present invention. Suitable protein kinase C-β inhibitors are, for example, LY333531.
[117] Any AMP-activated protein kinase activator can be used as the second compound of the combination of the present invention. Suitable activators are, for example, 5-amino-4-imidazolecarboxamide ribonucleosides.
[118] Any weight loss agent can be used as the second compound of the combination of the present invention. Suitable weight loss agents include sibutramine and orlistat.
[119] Any dipeptidyl peptidase IV (DPPIV) inhibitor can be used as the second compound of the combination of the present invention. Suitable DPPIV inhibitors include NVP DPP728 and P32 / 98.
[120] Any glucagon antagonist may be used as the second compound of the combination of the present invention. Suitable glucagon antagonists are, for example, NNC25-2504.
[121] Any IKK-β inhibitor can be used as the second compound of the combination of the present invention. Suitable IKK-β inhibitors are, for example, salicylates.
[122] Any PTP1B inhibitor can be used as the second compound of the combination of the present invention. Suitable PTP1B inhibitors are, for example, PTP112.
[123] Any glycogen synthase kinase-3 (GSK-3) inhibitor can be used as the second compound of the combination of the present invention. Suitable GSK-3 inhibitors are, for example, Chir98014.
[124] Any GLP-1 agonist can be used as the second compound of the combination of the present invention. Suitable GLP-1 agonists include GLP1, NN-2211 and exendin 4.
[125] Any PPAR- [gamma] agent can be used as the second compound of the combination of the present invention. Suitable PPAR- [gamma] agents include Lesulin®, Avandia®, Actose® or CS011.
[126] Any PPAR- [gamma] antagonist can be used as the second compound of the combination of the present invention. Suitable PPAR- [gamma] antagonists are, for example, bisphenol A diglycidyl ether (BADGE).
[127] Any PPAR-α agonist can be used as the second compound of the combination of the present invention. Suitable PPAR-α agonists are, for example, fenofibrate.
[128] Any dual PPAR-α / PPAR-γ agonist may be used as the second compound of the combination of the present invention. Suitable dual agents include paglithasar, GW1929, DRF2725, AZ242 and KRP 297.
[129] Any RXR antagonist can be used as the second compound of the combination of the present invention. Suitable RXR antagonists are, for example, HX531.
[130] Any glycogen phosphorylase inhibitor can be used as the second compound of the combination of the present invention. Suitable glycogen phosphorylase inhibitors are, for example, CP-316819.
[131] Any sorbitol dehydrogenase inhibitor (SDI) can be used as the second compound of the combination of the present invention. Suitable SDl include those described in WO 00/59510. Particularly preferred SDl is 1R- (4- (4- (4,6-dimethyl)-[1,3,5] triazin-2-yl) -2R, 6S-dimethyl-piperazin-1-yl) -pyridine Midin-2-yl) -ethanol.
[132] Any aldose reductase inhibitor (ARI) can be used as the second compound of the combination of the present invention. Suitable ARIs include zopolet, epalestat, ponalestat, genarestat or fidarestat.
[133] Other ARIs suitable for use as the second compound of the combination of the present invention include compounds of the formula, prodrugs thereof, and pharmaceutically acceptable salts of said compounds and prodrugs:
[134]
[135] Where
[136] A is S, SO or SO ₂ ;
[137] R ¹ and R ² are each independently hydrogen or methyl;
[138] R ³ is Het ¹ , —CHR ⁴ Het ¹ or NR ⁶ R ⁷ ;
[139] R ⁴ is hydrogen or (C ₁ -C ₃ ) alkyl;
[140] R ⁶ is (C ₁ -C ₆ ) alkyl, aryl or Het ² ;
[141] R ⁷ is Het ³ ;
[142] Het ¹ is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnarinyl, naphthyridinyl, pterridinyl, pyrazinopyrazinyl, Pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thia Zolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxdiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl , Indazolyl, benzisoxazolyl, benzisothiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazole Lopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, tier Pyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, Imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, Imidazolopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl; Het ¹ is halo, formyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkylenyloxycarbonyl, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkyl, C (OH) R ¹² R ¹³ , (C ₁ -C ₄ ) alkylcarbonylamido, (C ₃ -C ₇ ) cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl, naphthyl, imido Dazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxdiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl , Isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, (C ₁ -C ₄ ) alkylsulphenyl, (C ₁ -C ₄ ) Alkylsulfonyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₆ ) alkyl which may be substituted with up to 3 fluorine or (C ₁ -C ₄ ) which may be substituted with up to 5 fluorine Up to 4 substituents each independently selected from alkoxy; Benzyl, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadizolyl, thidiazolyl, tetrazolyl in the definition of the substituent of Het ¹ , Thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, hydroxy , Halo, hydroxy- (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkyl, (C ₁ -C ₆ ) alkylsulphenyl, (C ₁ -C ₆ ) Alkylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ ) alkyl which may be substituted with up to 5 fluorine and (C ₁ -C which may be substituted with up to 5 fluorine ₆ ) may be substituted with up to 3 substituents independently selected from alkoxy; In the definition of the Het ¹ substituent, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl are hydroxy, halo, (C ₁ -C ₆ ) alkyl, hydroxy- (C ₁ -C ₄ ) alkyl , (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkyl, or the phenyl moiety is one Cl, Br, OMe, Me or SO ₂ -phenyl (the SO ₂ -phenyl is a phenyl moiety Cl , Br, OMe, Me, (C ₁ -C ₄ ) alkyl which may be substituted with up to 5 fluorine, or (C ₁ -C ₄ ) alkoxy which may be substituted with up to 3 fluorine Or up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl-phenyl, which may be substituted by; R ¹² and R ¹³ are each independently hydrogen or (C ₁ -C ₄ ) alkyl;
[143] Het ² and Het ³ are each independently imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxdiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothia Zolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy or thiophenoxy; Het ² and Het ³ are each independently halo, formyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkylenyloxycarbonyl, (C ₁ -C ₄ ) alkoxy- (C _1- C ₄ ) alkyl, C (OH) R ¹⁸ R ¹⁹ , (C ₁ -C ₄ ) alkylcarbonylamido, (C ₃ -C ₇ ) cycloalkylcarbonylamido, phenylcarbonylamido, phenyl , Naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, Pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, (C ₁ -C ₄ ) alkylsulphenyl, (C _1- C ₄ ) alkylsulfonyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₄ ) alkyl which may be substituted with up to 3 fluorine or (C which may be substituted with up to 5 fluorine ₁ -C ₄ ) substituted with up to ₄ substituents each independently selected from alkoxy Can be; Phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadizolyl, thidiazolyl, tetra in the definition of the substituents of Het ² and Het ³ Zolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy Hydroxy, halo, hydroxy- (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ which may be substituted with up to 5 fluorine Or up to 3 substituents independently selected from (C ₁ -C ₄ ) alkoxy, which may be substituted by alkyl or up to 5 fluorine; Imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of the substituents of Het ² and Het ³ are hydroxy, halo, hydroxy- (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄₎ alkoxy - (C ₁ -C ₄₎ which may be substituted with alkyl, no more than 5 fluorine (C ₁ -C ₄₎ which may be substituted with alkyl, or up to three fluorine (C ₁ -C ₄₎ May be substituted with up to 2 substituents independently selected from alkoxy; R ¹⁸ and R ¹⁹ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, provided that when R ³ is NR ⁶ R ⁷ Is SO ₂ . A particularly suitable compound of formula ARI for use as the second compound of the combination of the present invention is 6- (5-chloro-3-methyl-benzofuran-2-sulfonyl) -2H-pyridazin-3-one.
[144] Any soluble guanylate cyclase (sGC) activator can be used as the second compound of the combination of the present invention. Suitable sGC activators include BAY 41-2272 and BAY 41-8543.
[145] Any growth hormone secretagogue can be used as the second compound of the combination of the present invention. Suitable growth hormone secretagogues are described in US Pat. No. 6,124,264; No. 6,110,932; 6,278,000; And 6,251,902. Particularly preferred growth hormone secretagogues are 2-amino-N- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo- [4,3c] pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramid.
[146] Particularly preferred compounds for use as the second compound in the combinations and pharmaceutical compositions according to the invention are insulin sensitizers, PDE5 inhibitors, protein kinase C-β inhibitors, AMP-activated protein kinase activators, insulin, body weight as described above Reducing agents, PPAR-γ agonists, PPAR-α agonists, dual PPAR-γ / PPAR-α agonists, sorbitol dehydrogenase inhibitors and aldose reductase inhibitor compound groups.
[147] PDE9 Inhibitors-Test Methods
[148] Phosphodiesterase (PDE) inhibitory activity
[149] Preferred PDE compounds for use according to the invention are potent cGMP PDE9 inhibitors. In vitro PDE inhibitory activity against cyclic guanosine 3 ', 5'-monophosphate (cGMP) and cyclic adenosine 3', 5'-monophosphate (cAMP) phosphodiesterase was determined by IC ₅₀ values (enzyme activity). Concentration of compound required for 50% inhibition).
[150] Phosphodiesterase 9 can be generated from full length human recombinant clones transfected into SF9 cells, as described in Fisher et al., Journal of Biological Chemistry, 1998, 273, 15559-15564.
[151] Direct detection of AMP / GMP either by modifying the "batch" method of WJ Thompson et al. (Biochem., 1979, 18 , 5228) or by modifying the protocol described by Amersham plc under the product code TRKQ7090 / 7100. The analysis is performed using a flash approach assay. In summary, substrates at various concentrations of inhibitors and at levels low enough that the IC ₅₀ is nearly K _i (cGMP with a 3: 1 ratio of the unlabeled to [ ³ H] -labeled at a concentration of about 1/3 K _m ). The effect of the PDE9 inhibitor is studied by analyzing the amount of enzyme fixed in the presence of. The final assay volume is brought to 100 μl with assay buffer (20 mM Tris-HCI pH 7.4, 5 mM MgCl ₂ , 1 mg / ml bovine serum albumin). Initiate the reaction with enzyme, incubate at 30 ° C. for 30-60 minutes to obtain less than 30% substrate conversion and contain 50 μl yttrium silicate SPA beads (3 mM of each unlabeled cyclic nucleotide for PDE 9 and 11) The reaction was terminated with). The plates were resealed and shaken for 20 minutes, after which the beads were allowed to settle for 30 minutes in the dark and counted with a top count plate reader (Packard, Meriden, CT). Radioactivity units were converted to% active of non-inhibited control (100%), plotted against inhibitor concentration, and inhibitor IC ₅₀ values were obtained using a 'Fit Curve' Microsoft Excel extension.
[152] Effect of specific PDE9 inhibitors on insulin resistance syndrome in animals- ob / obEffect on Plasma Glucose, Triglycerides, Insulin, and cGMP Levels in Mice
[153] Biological data
[154] Experimental protocol
[155] Test compound :
[156] The PDE9 inhibitor compound to be tested was dissolved in 10% DMSO / 0.1% Pluronix and administered by oral gavage using mouse oral feeding saliva (20 gauge, Popper & Sons, Inc., New Hyde Park, NY). 4 ml / kg body weight was administered for each dose. Compounds were tested at doses in the range of 1-50 mg / kg.
[157] Experimental Animals :
[158] Male ob / ob mice obtained from Jackson Laboratories (Bar Harbor, ME) were used in the study at 6-10 week ages. Mice were housed at 5 per cage and had free access to D11 mouse food (Purina, Brentwood, Mo.) and water.
[159] Experimental protocol :
[160] Mice were acclimated to Pfizer animal facilities for one week prior to the start of the test. On day 1, orbital posterior blood samples were obtained and plasma glucose was measured as described below. Mice were divided into 5 groups so that the mean plasma glucose concentration of each group did not differ. On day 1, vehicle or test PDE9 inhibitor compounds were administered to mice only in the afternoon. The mice were then dosed twice daily in the morning and afternoon on days 2-4. On day 5, mice were dosed in the morning and blood was collected 3 hours later for plasma and aliquots of glucose and triglyceride assays as described below. On day 5 final plasma samples were collected after orbital posterior bleeding as described below. Body weights were measured on days 1 and 5 of the test and food consumption was assessed over 5 days.
[161] Final blood collection and tissue collection
[162] On the morning of the last day of the test, the test compound or vehicle was dosed around 8 am. Three hours after dosing, 25 μl of blood was obtained from the orbital posterior sinus and added to 100 μl of 0.025% heparinized saline in Denville Scientific microtubes. The tube was spun at full speed in Beckman Microfuge 12 for 2 minutes. Plasma was collected for blood glucose and triglyceride measurements. Mice were sacrificed by the guillotine and about 1 ml of blood was collected in a Becton-Dickinson Microtainer brand plasma separator tube containing lithium heparin. The tube was spun at full speed in a Beckman microfuge 12 for 5 minutes. Plasma was collected in 1.5 ml Eppendorf tubes and snap frozen in liquefied nitrogen. Plasma samples were stored at −80 ° C. until analysis.
[163] Metabolite and Horbon Analysis :
[164] Plasma glucose and triglycerides were measured using an Alcion Clinical Chemical Analyzer (Abbott Laboratories, Abbott Park, IL) using a kit supplied by Abbott. Plasma cGMP was measured using a Biotrak enzyme-immunoassay system by Amersham (Piscataway, NJ). Plasma insulin was assessed by the Mercodia ELISA insulin kit by ALPCO (Uppsala, Sweden) by a similar technique. All analyzes were performed according to the instructions provided by the manufacturer.
[165] result
[166] Table 1 shows plasma over five days observed at [4,3-d] pyrimidin-7-one with Compound A, 5- (3-chloro-benzyl) -3-isopropyl-1,6-dihydropyrazolo Changes in glucose, triglyceride and insulin levels.
[167] Taken together, experimental results in hyperglycemic, insulin-resistant ob / ob mice suggest that selective PDE9 inhibitors improve metabolic parameters associated with IRS.
[168] process Plasma Glucose (mg / dl) Plasma Triglycerides (mg / dl) Plasma insulin (pmol / ml) Vehicle 370 ± 23 207 ± 9 12.0 ± 1.5 Compound A (10 mg / kg) 304 ± 17 155 ± 8 8.2 ± 1.5
[169] The data in Table 1 is the standard error of the mean ± mean.
[170] Table 2 shows the increase in plasma cGMP by 5-day treatment of 5- (3-chloro-benzyl) -3-isopropyl-1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one Indicates.
[171] process Plasma cGMP (pmol / ml) Vehicle 9.8 ± 0.5 Compound A (10 mg / kg) 16.8 ± 3.1
[172] The data in Table 2 is the standard error of the mean ± mean.
[173] General Process for Preparation of Examples 1-77
[174]
[175] Carboxylic acid (80 μmol) was dissolved in a 3.75% solution of triethylamine in dimethylacetamide (400 μl) and added to a 96 well plate. Carbonyldiimidazole (13 mg, 80 μmol) dissolved in pyridine (212 μl) was added to each well and the plate was left at room temperature for 2 hours. 4-amino-5-isopropyl-2H-pyrazole-3-carboxylic acid amide (13.5 mg, 80 μmol) dissolved in dimethylacetamide (100 μl) is added, the plate is sealed and in an oven under nitrogen Heated to 70 ° C. This was kept for 18 hours, the plate was taken out and cooled to room temperature (2 hours). Solvent was removed over 5.5 hours using GENEVAC (45 ° C., 0.15 mbar). A solution of potassium t-butoxide (268 mg, 240 μmol) in isopropyl alcohol (0.5 ml) was added to each well, the plate was sealed and transferred to an oven at 110 ° C. under nitrogen. This was kept for 15 hours, and the plate was taken out and cooled to room temperature (2 hours). The solvent was again removed over 5.5 hours using GENEVAC (45 ° C., 0.15 mbar) and a solution of p-toluenesulfonic acid (30 mg, 160 μl) in isopropyl alcohol (0.5 ml) was added to each well. The plate was left at room temperature for 18 hours and the solvent was removed over 5.5 hours using GENEVAC (45 ° C., 0.15 mbar). The residue was dissolved in dimethylsulfoxide (450 μl per well) and each compound was purified by preparative HPLC. Compounds were characterized by LC-MS analysis.
[176] Preparative HPLC Conditions
[177] Column: Phenomenex Luna C18, 5 μm, 150 x 10 mm id
[178] Temperature: ambient temperature
[179] Eluent A: 0.05% diethylamine (aqueous)
[180] Eluent B: acetonitrile
[181] Sample solvent: 90% dimethyl sulfoxide in water
[182] Initial Pump Conditions: A% 90, B% 10, Flow 6 ml / min
[183] Detection: Gilston 119 UV Detector-225 nm
[184] Injection volume-600 μl
[185] Gradient timetable
[186] Time (min)A%B%Flow (ml / min) 0.09556 0.29556 7.05956 9.05956 9.19556 10.59556
[187] LC-MS conditions
[188] Column: Phenomenex Luna C18, 5 μm, 30 × 4.6 mm id.
[189] Temperature: 40 ℃
[190] Eluent A: 0.05% diethylamine (aqueous)
[191] Eluent B: acetonitrile
[192] Initial pump conditions: A% 90, B% 10, flow 3 ml / min
[193] Injection volume-5 μl
[194] Detection: 210 nm start range, 280 nm end range, 5 nm range interval, 0.1 mAU threshold, 0.4 min peak width.
[195] Gradient timetable
[196] Time (min)A%B%Flow (ml / min)Pressure (bar) 0.090103400 2.25953400 2.45953400 2.590103400
[197] ELSD: Sedere Dedex 55, temperature: 40 ° C., gas flow: 2.3 bar
[198] MS: platform LC, ES + cone voltage: 26v, capillary: 4.08kv
[199] ES- cone voltage: -24v, capillary: -3.58kv
[200] Cover gas: 500 l / min, temperature: 130 ℃
[201]
[202]
[203]
[204]
[205]
[206]
[207]
[208]
[209]
[210]
[211]
[212]
[213]
[214]
[215]
[216]
[217] General Process for the Preparation of Examples 78-159
[218]
[219] Carboxylic acid (80 μmol) was dissolved in a 3.75% solution of triethylamine in dimethylacetamide (400 μl) and added to a 96 well plate. Carbonyldiimidazole (13 mg, 80 μmol) dissolved in pyridine (212 μl) was added to each well and the plate was left at room temperature for 2 hours. A 5-substituted-4-amino-pyrazole-3-carboxamide (80 μmol) solution dissolved in dimethylacetamide (100 μl) was added, the plate was sealed and heated to 70 ° C. in an oven under nitrogen. . This was kept for 18 hours, the plate was taken out and cooled to room temperature (2 hours). Solvent was removed over 11 hours using GENEVAC (30 ° C., 0.15 mbar). A solution of potassium t-butoxide (268 mg, 240 μmol) in isopropyl alcohol (0.5 ml) was added to each well, the plate was sealed and transferred to an oven at 110 ° C. under nitrogen. This was kept for 15 hours, and the plate was taken out and cooled to room temperature (2 hours). Solvent was removed again over 11 hours using GENEVAC (30 ° C., 0.15 mbar) and a solution of p-toluenesulfonic acid (30 mg, 160 μl) in isopropyl alcohol (0.5 ml) was added to each well. The plate was left at room temperature for 18 hours and the solvent was removed over 11 hours using GENEVAC (30 ° C., 0.15 mbar). The residue was dissolved in dimethylsulfoxide (450 μl per well) and each compound was purified by preparative HPLC. Compounds were characterized by LC-MS analysis.
[220] Preparative HPLC Conditions
[221] Column: Phenomenex Luna C18, 5 μm, 150 × 10 mm id
[222] Temperature: ambient temperature
[223] Eluent A: 0.05% diethylamine (aqueous)
[224] Eluent B: acetonitrile
[225] Sample solvent: 90% dimethyl sulfoxide in water
[226] Initial Pump Conditions: A% 90, B% 10, Flow 6 ml / min
[227] Detection: Gilstone 119 UV Detector-225 nm
[228] Injection volume-600 μl
[229] Gradient timetable
[230] Time (min)A%B%Flow (ml / min) 0.09556 0.29556 7.05956 9.05956 9.19556 10.59556
[231] LC-MS conditions
[232] Column: Phenomenex Luna C18, 5 μm, 30 × 4.6 mm id.
[233] Temperature: 40 ℃
[234] Eluent A: 0.05% diethylamine (aqueous)
[235] Eluent B: acetonitrile
[236] Initial pump conditions: A% 90, B% 10, flow 3 ml / min
[237] Injection volume-5 μl
[238] Detection: 210 nm start range, 280 nm end range, 5 nm range interval, 0.1 mAU threshold, 0.4 min peak width.
[239] Gradient timetable
[240] Time (min)A%B%Flow (ml / min)Pressure (bar) 0.090103400 2.25953400 2.45953400 2.590103400
[241] ELSD: Ceder dedex 55, temperature: 40 ° C., gas flow: 2.3 bar
[242] MS: platform LC, ES + cone voltage: 26v, capillary: 4.08kv
[243] ES- cone voltage: -24v, capillary: -3.58kv
[244] Cover gas: 500 l / min, temperature: 130 ℃
[245]
[246]
[247]
[248]
[249]
[250]
[251]
[252]
[253]
[254]
[255]
[256]
[257]
[258]
[259]
[260]
[261]
[262] Example 160
[263] 3-cyclopentyl-5- (2-trifluoromethoxy-benzyl) -1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one
[264]
[265] 5-cyclopentyl-4- [2- (2-trifluoromethoxy-phenyl) -acetylamino] -1 H-pyrazole-3-carboxylic acid amide (120 mg, 0.303 mmol) and potassium tert-butoxide ( 102 mg, 0.909 mmol) was suspended in isopropyl alcohol (5 ml) and the reaction was heated to reflux for 18 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was removed, acidified to pH 2 with 2N HCl and extracted with ethyl acetate (2 × 15 ml). The combined organic extracts were washed with saturated sodium carbonate solution (3 × 10 ml), dried over MgSO ₄ , concentrated under reduced pressure and the residue was flash column chromatographed on silica gel with dichloromethane: methanol (95: 5 volume ratio) as eluent. Purification by chromatography gave 3-cyclopentyl-5- (2-trifluoromethoxy-benzyl) -1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one (21 mg). Obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.36-7.41 (2H, m), 7.29-7.36 (2H, m), 3.97-4.03 (2H, brs), 2.39-2.45 (1H, m, solvent Partially shielded by), 1.82-1.94 (2H, m), 1.66-1.79 (2H, m), 1.58-1.65 (2H, m), 1.49-1.58 (2H, m) ppm. LRMS (electrospray): m / z [M−H] ⁺ 377.
[266] Example 161
[267] 3-isobutyl-5- (2-trifluoromethoxy-benzyl) -1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one
[268]
[269] 5-isobutyl-4- [2- (2-trifluoromethoxy-phenyl) -acetylamino] -1 H-pyrazole-3-carboxylic acid amide (140 mg, 0.365 mmol) and potassium tert-butoxide ( 123 mg, 1.09 mmol) was suspended in isopropyl alcohol (6 ml) and the reaction was heated to reflux for 18 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was removed, acidified to pH 2 with 2N HCl and extracted with ethyl acetate (2 × 15 ml). The combined organic extracts were washed with saturated sodium carbonate solution (3 × 10 ml), dried over MgSO ₄ , concentrated under reduced pressure and the residue was flash column chromatographed on silica gel with dichloromethane: methanol (95: 5 volume ratio) as eluent. Purification by chromatography gave 3-isobutyl-5- (2-trifluoromethoxy-benzyl) -1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one (27 mg). Obtained as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.64-8.74 (1 H, brs), 7.22-7.41 (4H, m, partially shielded by solvent), 4.15 (2H, s), 2.79-2.84 ( 2H, d), 2.13-2.23 (1H, m), 0.92-1.00 (6H, d) ppm. LRMS (electrospray): m / z [M + H] ⁺ 367, [MH] ⁺ 365.
[270] Example 162
[271] 3-pyridin-3-yl-5- (2-trifluoromethoxy-benzyl) -1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one
[272]
[273] 5-Pyridin-3-yl-4- [2- (2-trifluoromethoxy-phenyl) -acetylamino] -1 H-pyrazole-3-carboxylic acid amide (345 mg, 0.85 mmol) and potassium tert- Butoxide (286 mg, 2.55 mmol) was suspended in isopropyl alcohol (5 ml) and the reaction was heated to 55 ° C. for 18 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was removed, acidified to pH 2 with 2N HCl and extracted with ethyl acetate (2 × 15 ml) and dichloromethane (2 × 15 ml). The combined organic extracts were dried over MgSO ₄ , concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane: methanol (change from 99: 1 volume ratio to 95: 5 volume ratio). . The product was triturated with methanol (3 ml), dichloromethane (3 ml) and diethyl ether (3 ml) to give 3-pyridin-3-yl-5- (2-trifluoromethoxy-benzyl) -1,6 -Dihydro-pyrazolo [4,3-d] pyrimidin-7-one (13 mg) was obtained as an off-white solid. ¹ H NMR (400 MHz, CD ₃ 0D): δ = 9.34 (1H, brs), 8.57-8.61 (1H, d), 8.43-8.48 (1H, m), 7.32-7.47 (5H, m), 4.18 (2H , s) ppm. LRMS (electrospray): m / z [M−H] ⁺ 386.
[274] Manufacture 1
[275] 4-Methyl-3-oxo-pentanoic acid ethyl ester
[276]
[277] Sodium pellet (3.39 g, 148 mmol) was dissolved in ethanol (100 ml) at room temperature under nitrogen and diethyloxalate (20 ml, 147 mmol) in 3-methyl-2-butanone (18.9 ml, 177 mmol). The solution was added dropwise over 30 minutes at room temperature. The reaction was diluted with ethanol (100 ml), heated to 60 ° C. and stirred at this temperature for 2 hours. After cooling to room temperature, the reaction was poured into ice cold 2N HCl (200 ml) and extracted with diethyl ether (300 ml) and ethyl acetate (300 ml). The combined organic extracts were dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane: ethyl acetate (change from 99: 1 volume ratio to 95: 5 volume ratio). , 4-methyl-3-oxo-pentanoic acid ethyl ester (23.8 g) was obtained as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 14.40-14.80 (1H, brs), 6.40 (1H, s), 4.30-4.39 (2H, quart), 2.60-2.71 (1H, quin), 1.35-1.40 ( 3H, t), 1.15-1.20 (6H, d) ppm. LRMS (electrospray): m / z [M−H] ⁺ 185.
[278] Manufacture 2
[279] 5-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester
[280]
[281] Hydrazine hydrate (6.6 ml, 134 mmol) was added to a solution of 4-methyl-oxo-pentanoic acid ethyl ester (23.8 g, 188 mmol) in ethanol (100 ml) at room temperature under nitrogen. The reaction was allowed to proceed for 18 hours at room temperature and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (300 ml) and water (300 ml) and the aqueous phase was removed. The organic phase was washed with water (2 × 200 ml), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane: ethyl acetate (change from 4: 1 volume ratio to 2: 1 volume ratio) to 5-isopropyl-1H-pyrazole-3-carboxyl Acid ethyl ester (18.9 g) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 10.80-10.95 (1H, brs), 6.61 (1H, s), 4.33-4.40 (2H, quart), 2.98-3.08 (1H, quin), 1.35-1.41 ( 3H, t), 1.24-1.32 (6H, d) ppm. LRMS (electrospray): m / z [M−H] ⁺ 181.
[282] Manufacture 3
[283] 5-isopropyl-1H-pyrazole-3-carboxylic acid
[284]
[285] 5-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester (18.9 g, 104 mmol) and 1M NaOH solution (260 ml, 259 mmol) were dissolved in 1,4-dioxane (300 ml), The reaction was heated to 50 ° C. under nitrogen and stirred for 3 hours. The reaction mixture was cooled down, adjusted to pH 2 with concentrated sulfuric acid, and the solvent was removed under reduced pressure. The residual solid was azeotropic with toluene (2 x 30 ml), dissolved in ethyl acetate (500 ml) and washed with water (200 ml). The aqueous phase was removed, extracted with ethyl acetate (2 × 200 ml) and the combined organic extracts were dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was azeotropic with dichloromethane (2 x 50 ml) to afford 5-isopropyl-1H-pyrazole-3-carboxylic acid (14.7 g) as a white solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.50-13.30 (2H, brs), 6.42 (1H, s), 2.84-2.94 (1H, quin), 1.15-1.19 (6H, d) ppm. LRMS (electrospray): m / z [M−H] ⁺ 153.
[286] Manufacture 4
[287] 5-isopropyl-4-nitro-1H-pyrazole-3-carboxylic acid
[288]
[289] 5-isopropyl-1H-pyrazole-3-carboxylic acid (5 g, 32.5 mmol) was added portionwise to concentrated sulfuric acid (25 ml) with stirring at room temperature. The reaction mixture was heated to 60 ° C. and concentrated nitric acid (70%, 6 ml, 90 mmol) was added dropwise while maintaining the temperature at 60 ° C. The reaction was stirred at 60 ° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes, the white precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-isopropyl-4-nitro-1H-pyrazole-3-carboxylic acid (5.2 g) as a white solid. . ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 13.86-13.93 (1H, brs), 13.50-13.80 (1H, brs), 3.39-3.52 (1H, m), 1.18-1.30 (6H, d) ppm . LRMS (electrospray): m / z [M−H] ⁺ 198.
[290] Manufacture 5
[291] 5-isopropyl-4-nitro-1H-pyrazole-3-carboxylic acid amide
[292]
[293] Oxalyl chloride (6.8 ml, 77.6 mmol) under nitrogen at 0 ° C., 5-isopropyl-4-nitro-1H-pyrazole-3-carboxol in dichloromethane (80 ml) containing dimethylformamide (0.1 ml) To the suspension of acid (5.15 g, 25.9 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 1 h, warmed to rt and further stirred for 2 h. The solvent was removed under reduced pressure, the residue was dissolved in toluene (100 ml) and ammonia gas was bubbled into the solution for 2 hours. The reaction was stirred at rt under nitrogen for 18 h, concentrated under reduced pressure and the residue dissolved in hot methanol (300 ml). The resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was azeotropic with water (300 ml), concentrated to about 80 ml under reduced pressure, and the precipitate was isolated by filtration. It was washed with water and dried to give 5-isopropyl-4-nitro-1H-pyrazole-3-carboxylic acid amide (3. 1 g) as an orange solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 7.94-7.99 (1H, brs), 7.68-7.72 (1H, brs), 3.45-3.55 (1H, m), 1.24-1.30 (6H, d) ppm . LRMS (electrospray): m / z [M + Na] ⁺ 221, [MH] ⁺ 197.
[294] Manufacture 6
[295] 4-Amino-5-isopropyl-1 H-pyrazole-3-carboxylic acid amide
[296]
[297] 5-Isopropyl-4-nitro-1H-pyrazole-3-carboxylic acid amide (3 g, 15.1 mmol) and 10% palladium on carbon (500 mg) in ethanol (30 ml) were added to hydrogen (50 psi) at room temperature. Stirred for 18 hours. The reaction mixture was filtered and the solid was washed with methanol (50 ml), dichloromethane (50 ml), ethanol (50 ml) and ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol (9: 1 volume ratio) to give 4-amino-5-isopropyl-1H-pyrazole-3-carr Acid amide (2.6 g) was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.20-12.30 (1H, brs), 7.02-7.14 (1H, brs), 6.85-6.95 (1H, brs), 4.30-4.46 (2H, brs), 2.90-3.00 (1H, m), 1.15-1.21 (6H, d) ppm. LRMS (electrospray): m / z [MH] + 167, [2M-H] + 335. Found C, 49.86; H, 7. 21; N, 33.07. C ₇ H ₁₂ N ₄ 0 is C, 49.99; H, 7. 19; N, required 33.31%.
[298] Manufacture 7
[299] 3-oxo-heptanoic acid ethyl ester
[300]
[301] Sodium pellet (3.82 g, 166 mmol) was dissolved in ethanol (100 ml) under nitrogen at room temperature, and a solution of hexane-2-one (20 g, 198 mmol) and diethyloxalate (22.6 ml, 166 mmol) was added to room temperature. Was added dropwise over 30 minutes. The reaction was diluted with ethanol (100 ml), heated to 60 ° C. and stirred at this temperature for 2 hours. After cooling to room temperature, the reaction was poured into ice cold 2N HCl (200 ml) and extracted with diethyl ether (300 ml) and ethyl acetate (300 ml). The combined organic extracts were dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane: ethyl acetate (change from 99: 1 volume ratio to 95: 5 volume ratio). , 3-oxo-peptanoic acid ethyl ester (30.3 g) was obtained as an orange oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 14.30-14.80 (1H, brs), 6.37 (1H, s), 4.30-4.39 (2H, quart), 2.43-2.50 (2H, t), 1.59-1.62 ( 2H, quin), 1.31-1.40 (5H, t + m), 0.86-0.97 (3H, t) ppm. LRMS (electrospray): m / z [M−H] ⁺ 199.
[302] Manufacture 8
[303] 5-butyl-1H-pyrazole-3-carboxylic acid ethyl ester
[304]
[305] Hydrazine hydrate (7.75 ml, 157 mmol) was added dropwise to a solution of 3-oxo-heptanoic ethyl ester (30 g, 150 mmol) in ethanol (100 ml) at room temperature under nitrogen. The reaction was heated to 50 ° C., reacted at this temperature for 18 hours, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (300 ml) and water (300 ml) and the aqueous phase was removed. The organic phase was washed with water (2 × 200 ml), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with pentane: ethyl acetate (8: 1 volume ratio) to give 5-butyl-1H-pyrazole-3-carboxylic acid ethyl ester (24 g) as a yellow oil. Got it. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 10.58-10.78 (1H, brs), 6.62 (1H, s), 4.35-4.40 (2H, quart), 2.63-2.70 (2H, t), 1.60-1.67 ( 2H, quin), 1.35-1.42 (5H, t + m), 0.90-0.96 (3H, t) ppm. LRMS (electrospray): m / z [M−H] ⁺ 195.
[306] Manufacture 9
[307] 5-Butyl-1H-pyrazole-3-carboxylic acid
[308]
[309] 5-butyl-1H-pyrazole-3-carboxylic acid ethyl ester (24 g, 122 mmol) and 1M NaOH solution (305 ml, 306 mmol) were dissolved in 1,4-dioxane (300 ml) and the reaction Heated to 55 ° C. under nitrogen and stirred for 2 h. The reaction mixture was cooled down, adjusted to pH 2 with concentrated sulfuric acid, and the solvent was removed under reduced pressure. The residual solid was dissolved in ethyl acetate (300 ml) and washed with water (300 ml). The aqueous phase was removed, extracted with ethyl acetate (300 ml) and the combined organic extracts were dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was azeotropic with dichloromethane (2 x 50 ml) to afford 5-butyl-1H-pyrazole-3-carboxylic acid (22.6 g) as a white solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.50-13.00 (2H, brs), 6.41 (1H, s), 2.47-2.57 (2H, t), 1.46-1.56 (2H, quin), 1.19- 1.29 (2H, sext), 1.15-1.19 (3H, t) ppm. LRMS (electrospray): m / z [M−H] ⁺ 167. Found C, 57.01; H, 7. 23; N, 16.50. C ₈ H ₁₂ N ₂ 0 ₂ is C, 57.13; H, 7. 19; N, requires 16.66%.
[310] Manufacture 10
[311] 5-Butyl-4-nitro-1H-pyrazole-3-carboxylic acid
[312]
[313] 5-butyl-1H-pyrazole-3-carboxylic acid (22.6 g, 134 mmol) was added portionwise to concentrated sulfuric acid (100 ml) with stirring at room temperature. The reaction mixture was heated to 60 ° C. and concentrated nitric acid (70%, 23.7 ml, 376 mmol) was added dropwise while maintaining the temperature at 60 ° C. The reaction was stirred at 60 ° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes, the pale yellow precipitate was isolated by filtration, washed with water and dried under reduced pressure to afford 5-butyl-4-nitro-1H-pyrazole-3-carboxylic acid (21.9 g) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 2.83-2.92 (2H, t), 1.56-1.64 (2H, quin), 1.22-1.36 (2H, sext), 0.84-0.90 (3H, t) ppm . LRMS (electrospray): m / z [M−H] ⁺ 212. Found C, 30.19; H, 5.41; N, 13.12. C ₈ H ₁₁ N ₃ 0 _4. 6 mol H ₂ 0 is C, 29.91; H, 7.22; N, requires 13.08%.
[314] Manufacture 11
[315] 5-butyl-4-nitro-1H-pyrazole-3-carboxylic acid amide
[316]
[317] Oxalyl chloride (12.3 ml, 141 mmol) under nitrogen at 0 ° C. in 5-chloro-4-nitro-1H-pyrazole-3-carboxyl in dichloromethane (100 ml) containing dimethylformamide (0.5 ml) To the acid (10 g, 46.9 mmol) suspension was added dropwise. The reaction was stirred at 0 ° C. for 1 h, warmed to rt and further stirred for 2 h. The solvent was removed under reduced pressure, the residue was dissolved in toluene (100 ml) and ammonia gas was bubbled into the solution for 2 hours. The reaction was stirred at room temperature under nitrogen for 18 hours, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol (9: 1 volume ratio) to 5-butyl-4-nitro. -1H-pyrazole-3-carboxylic acid amide (3. 1 g) was obtained as an orange solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 7.87-7.96 (1H, brs), 7.57-7.66 (1H, brs), 2.83-2.90 (2H, t), 1.56-1.63 (2H, quin), 1.24-1.36 (2H, sext), 0.84-0.92 (3H, t) ppm. LRMS (electrospray): m / z [M−H] ⁺ 211. Found C, 44.66; H, 5.56; N, 25.50. C ₈ H ₁₂ N ₄ 0 ₃ .0.23 mol H ₂ 0 is C, 44.41; H, 5.80; N, requires 25.90%.
[318] Manufacture 12
[319] 4-Amino-5-butyl-1 H-pyrazole-3-carboxylic acid amide
[320]
[321] 5-Butyl-4-nitro-1H-pyrazole-3-carboxylic acid amide (3.1 g, 17.0 mmol) and 10% palladium on carbon (600 mg) in ethanol (50 ml) were hydrogen (50 psi) at room temperature. Stir under 18 hours. The reaction mixture was filtered and the solid was washed with methanol (50 ml), dichloromethane (50 ml), ethanol (50 ml) and ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane: methanol (varied from 95: 5 volume to 90:10 volume ratio) to 4-amino-5-butyl -1H-pyrazole-3-carboxylic acid amide (2.37 g) was obtained as an orange solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.24-12.32 (1H, brs), 7.02-7.14 (1H, brs), 6.80-6.95 (1H, brs), 4.28-4.46 (2H, brs), 2.39-2.50 (2H, t, partially shielded by solvent), 1.45-1.56 (2H, quin), 1.22-1.35 (2H, next), 0.83-0.90 ppm. LRMS (electrospray): m / z [MH] + 181, [2M-H] + 363. Found C, 52.58; H, 7.80; N, 30.56. C ₈ H ₁₄ N ₄ O is C, 52.73; H, 7. 74; N, requires 30.75%.
[322] Manufacture 13
[323] 4,4-Dimethyl-3-oxo-pentanoic acid ethyl ester
[324]
[325] Sodium pellet (4.6 g, 200 mmol) was dissolved in ethanol (165 ml) at room temperature under nitrogen and a solution of diethyloxalate (27.2 ml, 200 mmol) in tert-butyl-methyl ketone (20.1 g, 200 mmol) Dropwise over 15 minutes at room temperature. The reaction was diluted with ethanol (100 ml), heated to 60 ° C. and stirred at this temperature for 2 hours. After cooling to rt, the reaction was stirred for 64 h, poured into ice cold 2N HCl (200 ml) and extracted with diethyl ether (3 × 200 ml). The combined organic extracts were washed with water, dried over MgSO ₄ and concentrated under reduced pressure to give 4,4-dimethyl-3-oxo-pentanoic acid ethyl ester (36.7 g) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 6.48 (1H, s), 4.26-4.37 (2H, quart), 1.29-1.38 (3H, t), 1.17 (9H, s) ppm. LRMS (electrospray): m / z [M + Na] ⁺ 223, [MH] ⁺ 199.
[326] Manufacture 14
[327] 5-tert-butyl-1H-pyrazole-3-carboxylic acid ethyl ester
[328]
[329] Hydrazine hydrate (9.5 ml, 180 mmol) was added to a solution of 4,4-dimethyl-3-oxo-pentanoic acid ethyl ester (36.7 g, 180 mmol) in ethanol (188 ml) at room temperature under nitrogen. The reaction was carried out at room temperature for 2 hours, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (500 ml) and water (400 ml) and the aqueous phase was removed. The organic phase was washed with brine (200 ml), dried over MgSO ₄ and concentrated under reduced pressure to afford 5-tert-butyl-1H-pyrazole-3-carboxylic acid ethyl ester (30.6 g) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 14.50-14.90 (1H, brs), 6.45 (1H, s), 4.25-4.31 (2H, quart), 1.27-1.36 (3H, t), 1.16 (9H, s) ppm. LRMS (thermal spray): m / z [M + H] ⁺ 197. Found C, 61.12; H, 8. 20; N, 14. 28. C ₁₀ H ₁₆ N ₂ 0 ₂ is C, 61.20; H, 8.22; N, requires 14.27%.
[330] Manufacture 15
[331] 5-tert-butyl-1H-pyrazole-3-carboxylic acid
[332]
[333] 5-tert-butyl-1H-pyrazole-3-carboxylic acid ethyl ester (20 g, 100 mmol) and 1M NaOH solution (250 ml, 250 mmol) were dissolved in 1,4-dioxane (300 ml), The reaction was heated to 60 ° C. under nitrogen and stirred for 2.5 h. The reaction mixture was cooled to rt and further stirred for 18 h. The reaction mixture was adjusted to pH 2 with concentrated sulfuric acid, extracted with ethyl acetate (4 x 200 ml) and the combined organic extracts washed with brine (100 ml). The organic phase was dried over MgSO ₄ and the solvent was removed under reduced pressure to give 5-tert-butyl-1H-pyrazole-3-carboxylic acid (14.7 g) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.80-12.88 (2H, brs), 6.41 (1H, s), 1.11 (9H, s) ppm. LRMS (electrospray): m / z [M + H] ⁺ 169, [M + Na] ⁺ 191, [MH] ⁺ 167.
[334] Manufacture 16
[335] 5-tert-butyl-4-nitro-1H-pyrazole-3-carboxylic acid
[336]
[337] 5-tert-butyl-1H-pyrazole-3-carboxylic acid (5 g, 29.7 mmol) was added portionwise to concentrated sulfuric acid (25 ml) with stirring at room temperature. The reaction mixture was heated to 60 ° C. and concentrated nitric acid (70%, 5.15 ml) was added dropwise while maintaining the temperature at 60 ° C. The reaction was stirred at 60 ° C. for 2.5 h, cooled to rt and poured into 50 ml of ice with stirring. After 15 minutes, the white precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-tert-butyl-4-nitro-1H-pyrazole-3-carboxylic acid (6.0 g) as a white solid. Got it. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 13.50-13.88 (2H, brs), 1.13 (9H, s) ppm. LRMS (electrospray): m / z [M + Na] ⁺ 236, [MH] ⁺ 212.
[338] Manufacture 17
[339] 5-tert-butyl-4-nitro-1H-pyrazole-3-carboxylic acid amide
[340]
[341] Oxalyl chloride (10.2 ml, 117 mmol) under nitrogen at 0 ° C. in 5-tert-butyl-4-nitro-1H-pyrazole-3- in dichloromethane (55 ml) containing dimethylformamide (0.1 ml) To the suspension of carboxylic acid (6 g, 28 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 0.5 h, warmed to rt and further stirred for 1.5 h. The solvent was removed under reduced pressure, the residue was azeotropic with dichloromethane (50 ml) and the residue was dissolved in dichloromethane (100 ml). Ammonia gas was bubbled into the solution for 45 minutes, the reaction was stirred at room temperature under nitrogen for 18 hours, concentrated under reduced pressure, and the residue dissolved in ethyl acetate (250 ml). After washing with water (100 ml) and brine (100 ml), the organic phase is filtered, the filtrate is dried over MgS0 ₄ and concentrated under reduced pressure, 5-tert-butyl-4-nitro-1H-pyrazole-3 -Carboxylic acid amide (4.0 g) was obtained as a light brown solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.90-13.08 (1H, brs), 7.78-7.86 (1H, brs), 7.49-7.60 (1H, brs), 1.30 (9H, s) ppm. LRMS (electrospray): m / z [M + H] ⁺ 213, [M + Na] ⁺ 235, [MH] ⁺ 211.
[342] Manufacture 18
[343] 4-Amino-5-tert-butyl-1H-pyrazole-3-carboxylic acid amide
[344]
[345] 5-tert-butyl-4-nitro-1H-pyrazole-3-carboxylic acid amide (4.6 g, 21 mmol) and 10% palladium on carbon (300 mg) in ethanol (80 ml) were added with hydrogen (60 psi) for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was pre-absorbed with silica gel and purified by flash column chromatography eluting with a solvent gradient of dichloromethane: methanol (change from 100: 0 volume ratio to 95: 5 to 90:10 volume ratio) to 4-amino-5- tert-Butyl-1H-pyrazole-3-carboxylic acid amide (2.96 g) was obtained as an off-white solid which is a rotamer mixture. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.10-12.20 (0.75H, brs), 11.75-11.85 (0.25H, brs), 7.04-7.16 (1.5H, brs), 6.88-6.96 (0.5H , brs), 4.27-4.59 (2H, 2xbrs), 1.12 (9H, s) ppm. LRMS (electrospray): m / z [M + H] ⁺ 183, [M + Na] ⁺ 205, [MH] ⁺ 181. Found C, 52.45; H, 7. 84; N, 30.62. C ₈ H ₁₄ N ₄ O is C, 52.73; H, 7. 74; N, requires 30.75%.
[346] Manufacture 19
[347] 5-Methyl-3-oxo-hexanoic acid ethyl ester
[348]
[349] Sodium pellets (4.6 g, 200 mmol) are dissolved in ethanol (165 ml) under nitrogen at room temperature and a solution of diethyloxalate (13.5 ml, 100 mmol) in isobutylmethyl ketone (30 ml, 200 mmol) at room temperature Dropwise over 20 minutes. The reaction was heated to 60 ° C. and stirred at this temperature for 1 hour. After cooling to room temperature, the reaction was poured into ice cold 2N HCl (200 ml) and extracted with diethyl ether (4 × 200 ml). The combined organic extracts were washed with water, dried over MgSO ₄ and concentrated under reduced pressure to give 5-methyl-3-oxo-hexanoic acid ethyl ester (20 g) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 14.40-14.70 (1H, brs), 6.27 (1H, s), 4.25-4.32 (2H, quart), 2.26-2.31 (2H, d), 2.02-2.18 ( 1H, m), 1.29-1.34 (3H, t), 0.89-0.94 (6H, d) ppm. LRMS (thermal spray): m / z [M + NH ₄ ] ⁺ 218.
[350] Manufacture 20
[351] 5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester
[352]
[353] Hydrazine hydrate (5.7 ml, 115 mmol) was added to a solution of 5-methyl-3-oxo-hexanoic acid ethyl ester (22 g, 110 mmol) in ethanol (113 ml) at room temperature under nitrogen. The reaction was carried out at room temperature for 18 hours, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (400 ml) and water (400 ml) and the aqueous phase was removed. The organic phase was washed with brine (200 ml), water (200 ml), dried over MgSO ₄ and concentrated under reduced pressure. The residue is eluted on a silica gel eluted with a solvent gradient of pentane: ethyl acetate (6: 1, 5: 1, 4: 1, 3: 1, 2: 1, finally 1: 1 volume ratio) at 1: 0 volume ratio. Purification by flash column chromatography gave 5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester (16.5 g) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 11.60-12.60 (1H, brs), 6.53 (1H, s), 4.26-4.35 (2H, quart), 2.48-2.54 (2H, d), 1.80-1.90 ( 1H, m), 1.25-1.31 (3H, t), 0.81-0.88 (6H, d) ppm. LRMS (thermal spray): m / z [M + H] ⁺ 197, [2M + H] ⁺ 393. Found C, 61.49; H, 8. 30; N, 14.24. C ₁₀ H ₁₆ N ₂ 0 ₂ is C, 61.20; H, 8.22; N, requires 14.27%.
[354] Manufacture 21
[355] 5-Isobutyl-1H-pyrazole-3-carboxylic acid
[356]
[357] 5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester (16.2 g, 83 mmol) and 1M NaOH solution (173 ml, 173 mmol) were dissolved in 1,4-dioxane (260 ml), The reaction was stirred at room temperature under nitrogen for 64 hours. The reaction mixture was adjusted to pH 7 with concentrated hydrochloric acid and concentrated under reduced pressure. Water (500 ml) was added, the slurry was adjusted to pH 1 with concentrated hydrochloric acid and the aqueous phase was extracted with ethyl acetate (5 x 300 ml). The combined organic extracts were dried over MgSO ₄ and the solvent was removed under reduced pressure to give 5-isobutyl-1H-pyrazole-3-carboxylic acid (10 g) as a white solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.72-12.90 (1H, brs), 6.39 (1H, s), 2.39-2.43 (2H, d), 1.77-1.86 (1H, m), 0.78- 0.83 (6H, d) ppm. LRMS (electrospray): m / z [M + Na] ⁺ 191, [2M + Na] ⁺ 359, [MH] ⁺ 167, [2M-H] ⁺ 335.
[358] Manufacture 22
[359] 5-isobutyl-4-nitro-1H-pyrazole-3-carboxylic acid
[360]
[361] 5-Isobutyl-1H-pyrazole-3-carboxylic acid (5 g, 29.7 mmol) was added portionwise to concentrated sulfuric acid (25 ml) with stirring at room temperature. The reaction mixture was heated to 60 ° C. and concentrated nitric acid (70%, 5.15 ml) was added dropwise while maintaining the temperature at 60 ° C. The reaction was stirred at 60 ° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. The resulting white precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-isobutyl-4-nitro-1H-pyrazole-3-carboxylic acid (6.4 g) as a white solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 2.71-2.76 (2H, d), 1.88-2.00 (1H, m), 0.80-0.87 (6H, d) ppm. LRMS (thermal spray): m / z [M + NH ₄ ] ⁺ 231, [MH] ⁺ 212. LRMS (electrospray): m / z [MH] ⁺ 212, [2M-H] ⁺ 425. Found C, 42.54; H, 5. 18; N, 18.63. C ₈ H ₁₁ N ₃ 0 ₄ .0.7 mol H ₂ O is C, 42.55; H, 5.54; N, 18.61% is required.
[362] Manufacture 23
[363] 5-isobutyl-4-nitro-1H-pyrazole-3-carboxylic acid amide
[364]
[365] Oxalyl chloride (10 ml, 115 mmol) under nitrogen at 0 ° C. in 5-chlorobutylmethane (70 ml) containing dimethylformamide (0.1 ml) 5-isobutyl-4-nitro-1H-pyrazole-3-carr To the suspension of acid (5.6 g, 26 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 0.5 h, warmed to rt and further stirred for 2 h. The solvent was removed under reduced pressure, the residue was azeotropic with dichloromethane (3 x 50 ml) and the residue was dissolved in toluene (100 ml). Ammonia gas was bubbled into the solution for 2 hours, the reaction was stirred at room temperature under nitrogen for 18 hours, concentrated under reduced pressure, and the residue suspended in methanol (250 ml). After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (400 ml) and washed with water (50 ml). The organic phase is filtered, the filtrate is dried over MgSO ₄ and concentrated under reduced pressure. The filtered solid and the residue from the filtrate were combined to give 5-isobutyl-4-nitro-1H-pyrazole-3-carboxylic acid amide (4.8 g) as an off-white solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 13.61-13.81 (1H, brs), 7.80-7.96 (1H, brs), 7.50-7.66 (1H, brs), 2.70-2.76 (2H, d), 1.90-2.01 (1 H, m), 0.83-0.88 (6 H, d) ppm. LRMS (electrospray): m / z [M + Na] ⁺ 235, [2M + Na] ⁺ 447, [MH] ⁺ 211, [2M-H] ⁺ 423. Found C, 45.12; H, 5.68; N, 26.31. C ₈ H ₁₂ N ₄ 0 ₃ is C, 45.28; H, 5. 70; N, 26.40% is required.
[366] Manufacture 24
[367] 4-Amino-5-isobutyl-1 H-pyrazole-3-carboxylic acid amide
[368]
[369] 5-Isobutyl-4-nitro-1H-pyrazole-3-carboxylic acid amide (4.7 g, 22 mmol) and 10% palladium on carbon (300 mg) in ethanol (80 ml) were hydrogen (60 psi) at room temperature. Stirring for 4 hours and maintaining under nitrogen for 64 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography eluting with a solvent gradient of dichloromethane: methanol (changes from 100: 0 to 95: 5 to 90:10 by volume) yielded 4-amino-5-isobutyl-1H-pyrazole- 3-carboxylic acid amide (3.8 g) was obtained as an off-white solid that is a rotamer mixture. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.20-12.28 (1H, brs), 7.00-7.10 (1.34H, brs), 6.80-6.85 (0.66H, brs), 4.27-4.40 (2H, brs ), 2.27-2.36 (2H, d), 1.78-1.88 (1H, m), 0.77-0.84 (6H, d) ppm. LRMS (electrospray): m / z [M + H] ⁺ 183, [M + Na] ⁺ 205. Found C, 52.27; H, 7.78; N, 30.59. C ₈ H ₁₄ N ₄ O is C, 52.73; H, 7.76; N, requires 30.75%.
[370] Manufacture 25
[371] 1-cyclopentylethanone
[372]
[373] Concentrated sulfuric acid (22.4 ml, 420 mmol) was added slowly to a solution of chromium trioxide (26.3 g, 263 mmol) dissolved in water (50 ml) at room temperature. After 10 minutes, this solution was added to 1-cyclopentylethanol (20 g, 175 mmol) dissolved in acetone (450 ml) while maintaining the temperature below 35 ° C. The addition was continued until the stepped orange lasted for 10 minutes. The reaction mixture was quenched with isopropyl alcohol to lose excess chromic acid and neutralized to pH 5 by the addition of sodium bicarbonate little by little. After filtration, the filtrate was concentrated under reduced pressure (50 ml) and extracted with diethyl ether (3 x 300 ml). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure to give 1-cyclopentylethanone (16.7 g) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.80-2.90 (1H, quin), 2.18 (3H, s), 1.53-1.86 (8H, 2 × m) ppm.
[374] Manufacture 26
[375] 3-cyclopentyl-3-oxo-propionic acid ethyl ester
[376]
[377] Sodium pellets (3.1 g, 135 mmol) were dissolved in ethanol (100 ml) at room temperature under nitrogen and a solution of diethyloxalate (18.4 ml, 135 mmol) and 1-cyclopentylethanone (16.7 g, 149 mmol) was added. It was added dropwise over 30 minutes at room temperature. The reaction was diluted with ethanol (100 ml), heated to 60 ° C. and stirred at this temperature for 2 hours. After cooling to room temperature, the reaction was poured into ice cold 2N HCl (200 ml) and extracted with diethyl ether (300 ml) and ethyl acetate (300 ml). The combined organic extracts were dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with pentane: ethyl acetate (6: 1 volume ratio) to give 3-cyclopentyl-3-oxo- Propionic acid ethyl ester (23.8 g) was obtained as an orange oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 14.38-14.65 (1H, brs), 6.83 (1H, s), 4.30-4.39 (2H, quart), 2.82-2.92 (1H, quin), 1.83-1.96 ( 2H, m), 1.57-1.83 (6H, 2xm), 1.33-1.40 (3H, t) ppm. LRMS (electrospray): m / z [M−H] ⁺ 211.
[378] Manufacture 27
[379] 5-cyclopentyl-1H-pyrazole-3-carboxylic acid ethyl ester
[380]
[381] Hydrazine hydrate (5.8 ml, 117 mmol) was added to a solution of 3-cyclopentyl-3-oxo-propionic acid ethyl ester (23.7 g, 112 mmol) in ethanol (100 ml) at room temperature under nitrogen. The reaction was carried out at room temperature for 18 hours, heated to 50 ° C. and maintained at this temperature for 4 hours. The solvent was removed under reduced pressure, and the residue was partitioned between dichloromethane (300 ml) and water (300 ml) and the aqueous phase removed. The organic phase was washed with water (2 × 200 ml), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane: ethyl acetate (4: 1 volume ratio) to give 5-cyclopentyl-1H-pyrazole-3-carboxylic acid ethyl ester (17.1 g). Was obtained as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 10.40-10.60 (1H, brs), 6.58 (1H, s), 4.30-4.38 (2H, quart), 3.01-3.10 (1H, quin), 2.00-2.10 ( 2H, m), 1.56-1.80 (6H, 2xm), 1.33-1.39 (3H, t) ppm. LRMS (electrospray): m / z [M + H] ⁺ 209, [M + Na] ⁺ 231. Found C, 63.40; H, 7.75; N, 13.41. C ₁₁ H ₁₆ N ₂ 0 ₂ is C, 63.44; H, 7. 74; N, requires 13.45%.
[382] Manufacture 28
[383] 5-cyclopentyl-1H-pyrazole-3-carboxylic acid
[384]
[385] 5-cyclopentyl-1H-pyrazole-3-carboxylic acid ethyl ester (17.1 g, 82 mmol) and 1M NaOH solution (205 ml, 205 mmol) were dissolved in 1,4-dioxane (300 ml), The reaction was heated to 50 ° C. under nitrogen and stirred for 3 hours. The reaction mixture was cooled down, adjusted to pH 2 with concentrated hydrochloric acid, and the solvent was concentrated under reduced pressure. The residual solid was azeotropic with toluene (2 x 30 ml), dissolved in ethyl acetate (500 ml) and washed with water (200 ml). The aqueous phase was removed, extracted with ethyl acetate (2 × 200 ml) and the combined organic extracts were dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was azeotropic with dichloromethane (2 x 50 ml) to afford 5-cyclopentyl-1H-pyrazole-3-carboxylic acid (13 g) as a white solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.75-12.88 (2H, brs), 6.43 (1H, s), 2.97-3.08 (1H, quin), 1.91-2.02 (2H, m), 1.50- 1.76 (6H, 2xm) ppm. LRMS (electrospray): m / z [M−H] ⁺ 179. Found C, 59.72; H, 6. 74; N, 15.37. C ₉ H ₁₂ N ₂ 0 ₂ is C, 59.99; H, 6.71; N, requires 15.55%.
[386] Manufacture 29
[387] 5-cyclopentyl-4-nitro-1H-pyrazole-3-carboxylic acid
[388]
[389] 5-cyclopentyl-1H-pyrazole-3-carboxylic acid (13 g, 72.1 mmol) was added portionwise to concentrated sulfuric acid (75 ml) with stirring at room temperature. The reaction mixture was heated to 60 ° C. and concentrated nitric acid (70%, 12.7 ml, 202 mmol) was added dropwise while maintaining the temperature at 60 ° C. The reaction was stirred at 60 ° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes, the precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-cyclopentyl-4-nitro-1H-pyrazole-3-carboxylic acid (7.1 g) as a yellow solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 14.00-14.41 (1H, brs), 13.28-13.85 (1H, brs), 3.20-3.56 (1H, brs, partially shielded by solvent), 1.96 -2.10 (2H, m), 1.54-1.80 (6H, 2xm) ppm. LRMS (electrospray): m / z [MH] + 224, [2M-H] + 449. Found C, 43.83; H, 5. 35; N, 16.94. C ₉ H ₁₁ N ₃ 0 ₄ .1.2 mol H ₂ O is C, 43.80; H, 5.47; N, requires 17.02%.
[390] Manufacture 30
[391] 5-cyclopentyl-4-nitro-1H-pyrazole-3-carboxylic acid amide
[392]
[393] Oxalyl chloride (7.65 ml, 87.7 mmol) under nitrogen at 0 ° C. in 5-isopropyl-4-nitro-1H-pyrazole-3-carboxol in dichloromethane (100 ml) containing dimethylformamide (0.5 ml) To the suspension of acid (6.58 g, 29.2 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 1 h, warmed to rt and further stirred for 2 h. The solvent was removed under reduced pressure and the residue was azeotropic with dichloromethane (2 x 50 ml) and dissolved in toluene (100 ml). Ammonia gas was bubbled into the solution for 2 hours, the reaction was stirred at room temperature under nitrogen for 18 hours, concentrated under reduced pressure, and with a solvent gradient of dichloromethane: methanol (change from 95: 5 volume ratio to 90:10 volume ratio). Purification by flash column chromatography on eluting silica gel yielded 5-cyclopentyl-4-nitro-1H-pyrazole-3-carboxylic acid amide (5.48 g) as a yellow solid. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 13.67-13.79 (1H, brs), 7.88-8.03 (1H, brs), 7.59-7.77 (1H, brs), 3.46-3.60 (1H, quin), 1.97-2.11 (2H, m), 1.58-1.81 (6H, 2xm) ppm. LRMS (electrospray): m / z [MH] + 223, [2M-H] + 447. Found C, 56.12; H, 7.39; N, 27.55. C ₉ H ₁₂ N ₄ 0 ₃ .0.2 mol acetone is C, 56.01; H, 7. 44; N, which requires 27.22%.
[394] Manufacture 31
[395] 4-Amino-5-cyclopentyl-1 H-pyrazole-3-carboxylic acid amide
[396]
[397] 5-cyclopentyl-4-nitro-1H-pyrazole-3-carboxylic acid amide (4.48 g, 20 mmol) and 10% palladium on carbon (800 mg) in ethanol (50 ml) were added to hydrogen (50 psi) at room temperature. Stirred for 18 hours. The reaction mixture was filtered through arbocel and the solid was washed with ethanol (50 ml), methanol (50 ml), dichloromethane (50 ml) and ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol (9: 1 volume ratio) to 4-amino-5-cyclopentyl-1H-pyrazole-3-carr Acid amide (4.0 g) was obtained as an off-white solid that is a rotamer mixture. ¹ H NMR (400 MHz, DMSO-D ₆ ): δ = 12.20-12.31 (0.75H, brs), 11.78-11.87 (0.25H, brs), 7.02-7.18 (1.5H, brs), 6.80-6.93 (0.5H , brs), 4.22-4.56 (2H, 2xbrs), 2.92-3.02 (1H, quin), 1.79-1.96 (2H, m), 1.48-1.78 (6H, 2xm) ppm. LRMS (electrospray): m / z [M−H] ⁺ 193. Found C, 56.12; H, 7.39; N, 27.55. C9H14N4O0.2 mol acetone is C, 56.01; H, 7. 44; N, which requires 27.22%.
[398] Manufacture 32
[399] (3-benzyloxy-phenyl) -acetic acid benzyl ester
[400]
[401] 3-hydroxy-phenyl-acetic acid (15.3 g, 101 mmol), benzyl bromide (36.2 g, 202 mmol) and potassium carbonate (29.2 g, 202 mmol) are suspended in dimethylformamide (300 ml) and the reaction is 44 h. Heated to reflux under nitrogen. The reaction mixture was cooled down, filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml) and the aqueous phase was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were washed with brine (200 ml), dried over Na ₂ SO ₄ , and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with pentane: ethyl acetate (95: 5 vol ratio) to give (3-benzyloxy-phenyl) -acetic acid benzyl ester (10.7 g) as a white solid.
[402] Manufacture 33
[403] (3-benzyloxy-phenyl) -acetic acid
[404]
[405] 1N sodium hydroxide solution (35 ml, 35 mmol) was added to a solution of (3-benzyloxy-phenyl) -acetic acid benzyl ester (5.3 g, 16 mmol) in methanol (350 ml) at room temperature under nitrogen. The reaction was heated to reflux for 2 hours and the solvent was removed under reduced pressure. The residue was dissolved in water (500 ml) and extracted with ether (3 x 350 ml). The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and the resulting precipitate was isolated by filtration and dried in vacuo to give (3-benzyloxy-phenyl) -acetic acid (3.08 g) as a white solid. -129 ° C. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.26-7.43 (5H, m), 7.20-7.26 (1H, m, partially shielded by solvent), 6.84-6.96 (3H, m + s), 5.04 (2H, s), 3.62 (2H, s) ppm. LRMS (electrospray): m / z [M−H] ⁺ 241. Found C, 74.21; H, 5.82. C ₁₅ H ₁₄ O is C, 74.36; H, requires 5.82%.
[406] Manufacture 34
[407] (4-hydroxy-3-methoxy-phenyl) -acetic acid methyl ester
[408]
[409] Concentrated sulfuric acid (12 ml) is added to a solution of (4-hydroxy-3-methoxy-phenyl) -acetic acid (22.5 g, 123 mmol) in methanol (450 ml) at room temperature and the reaction is brought to 90 ° C. for 2.45 h. Heated. The reaction was cooled to rt, stirred for 18 h and the solvent removed under reduced pressure. The residue was suspended in ice water (300 ml) and extracted with diethyl ether (2 x 300 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution (2 × 100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of cyclohexane: ethyl acetate (70:30, 60:40 at 80:20 volume ratio, finally 1: 1 volume ratio), (4- Hydroxy-3-methoxy-phenyl) -acetic acid methyl ester (23 g) was obtained as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 6.82-6.85 (1H, d), 6.80 (1H, s), 6.76-6.79 (1H, d), 5.49 (1H, s), 3.86 (3H, s) , 3.66 (3H, s), 3.53 (2H, s) ppm. LRMS (electrospray): m / z [M + Na] ⁺ 219.
[410] Manufacture 35
[411] (4-cyclopentyloxy-3-methoxy-phenyl) -acetic acid methyl ester
[412]
[413] Cyclopentanol (7.7 ml, 85 mmol) and triphenylphosphine (28 g, 107 mmol) were added (4-hydroxy-3-methoxy-phenyl)-in tetrahydrofuran (280 ml) under nitrogen at 0 ° C. Acetic acid methyl ester (14 g, 71 mmol) was added to the solution. Diethylazodicarboxylate (15.7 ml, 100 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 44 hours. The solvent was removed under reduced pressure, pentane (200 ml) was added and the suspension was filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel eluting with a solvent gradient of cyclohexane: ethyl acetate (change from 90:10 volume ratio to 85:15 volume ratio) to obtain (4-cyclopentyloxy-3 -Methoxy-phenyl) -acetic acid methyl ester (12.4 g) was obtained as a colorless oil. ¹ H NMR (400 MHz, CD ₃ 0D): δ = 6.79-6.85 (2H, m), 6.73-6.79 (1H, d), 4.73-4.79 (1H, brs), 3.79 (3H, s), 3.64 (3H , s), 3.53 (2H, s), 1.74-1.89 (6H, m), 1.56-1.67 (2H, m) ppm. LRMS (electrospray): m / z [M + Na] ⁺ 287. Found C, 68.01; H, 7.74. C ₁₅ H ₂₀ O ₄ is C, 68.16; H, required 7.63%.
[414] Manufacture 36
[415] (4-cyclopentyloxy-3-methoxy-phenyl) -acetic acid
[416]
[417] Sodium hydroxide (4.75 g, 119 mmol) was added to a solution of (4-cyclopentyloxy-3-methoxy-phenyl) -acetic acid methyl ester (12.4, 46.9 mmol) in methanol (100 ml) / water (100 ml) and The reaction was stirred at rt for 3.5 h. Methanol was removed under reduced pressure, and the aqueous phase was washed with diethyl ether (100 ml) and then acidified to pH 2 with concentrated hydrochloric acid. It is extracted with ethyl acetate (2 x 200 ml) and the combined organic extracts are washed with brine (100 ml), dried over Na ₂ S0 ₄ and concentrated under reduced pressure to give (4-cyclopentyloxy-3-methoxy -Phenyl) -acetic acid (11.1 g) was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ 0D): δ = 6.87 (1H, s), 6.81-6.86 (1H, d), 6.76-6.80 (1H, d), 4.75-4.79 (1H, brs), 3.78 (3H , s), 3.49 (2H, s), 1.71-1.89 (6H, m), 1.56-1.64 (2H, m) ppm. LRMS (electrospray): m / z [MH] + 249, [2M-H] + 499. Found C, 67.15; H, 7.25. C ₁₄ H ₁₈ 0 ₄ is C, 67.18; H, required 7.25%.
[418] Manufacture 37
[419] 2,4-dimethyl-phenyl-acetic acid
[420]
[421] 2,4-dimethylbenzylcyanide (70 g, 0.48 mol) was mixed with water (134 ml) and concentrated sulfuric acid (106 ml, 1.98 mol) was added slowly. The reaction was heated to reflux for 3 hours and cooled to room temperature over 18 hours. The mixture was poured into crushed ice (500 ml), stirred for 1 hour, and the resulting precipitate was isolated by filtration. After washing with water, the solid is dissolved in 1.2 M sodium hydroxide solution (500 ml), extracted with dichloromethane (2 x 250 ml), the aqueous phase is treated with decolorized carbon (2 g) for 10 minutes at reflux temperature and Filtration was performed with a hyflo supercel. The filtrate was acidified with concentrated hydrochloric acid and the resulting precipitate was isolated by filtration, washed with water and dried under vacuum to give 2,4-dimethyl-phenyl-acetic acid (52.6 g) as a white solid. ¹ H NMR (250 MHz, CD ₃ 0D / D ₂ 0): 8 = 6.88-7.03 (3H, m), 3.48-3.68 (2H, s), 2.23 (6H, s) ppm.
[422] Manufacture 38
[423] Benzene sulfonic acid 2-chloro-ethyl ester
[424]
[425] 2-chloroethanol (1168 g, 975 mol) and benzene sulfonyl chloride (2780 g, 2015 mol) were stirred together at -5 ° C and pyridine (2158 g, 2200 mol) was added to 3 while maintaining the temperature below 0 ° C. Add over time. The reaction was further stirred at −5 ° C. to 0 ° C. for 3 hours and then warmed to room temperature over 18 hours. After pouring into a mixture of ice (10 liters) and water (10 liters), the reaction is stirred for 15 minutes, extracted with ether (10 liters) and the organic phase is 5N HCl (2 x 2 liters) and water (2 x 4 Liters). It was dried over MgSO ₄ and concentrated under reduced pressure to give benzene sulfuric acid 2-chloro-ethyl ester (1921 g) as an orange oil. ¹ H NMR (250 MHz, CDCl ₃ ): δ = 7.78-8.02 (2H, m), 7.58-7.78 (3H, m), 4.20-4.45 (2H, t), 3.60-3.81 (2H, t) ppm.
[426] Manufacture 39
[427] 2-hydroxy-phenyl-acetic acid ethyl ester
[428]
[429] 2-hydroxy-phenyl-acetic acid (30.4 g, 0.2 mol) was dissolved in chloroform (200 ml) and thionyl chloride (50 ml, 0.2 mol) was added. The reaction was slowly refluxed for 2 hours and the mixture was concentrated under reduced pressure. The residue was poured slowly into ethanol (200 ml) while maintaining the temperature at 10-20 ° C. The solvent was removed under reduced pressure, and the residue was purified by thermal distillation to give 2-hydroxy-phenyl-acetic acid ethyl ester (31.6 g) as a yellow oil. Boiling point 146-150 ° C. V _max (thin film) 1710 cm ⁻¹ (C═O, ester).
[430] Manufacture 40
[431] [2- (2-Chloro-ethoxy) -phenyl] -acetic acid ethyl ester
[432]
[433] 50% sodium hydride (8.11 g, 169 mmol) in mineral oil was added in portions to a solution of 2-hydroxy-phenyl-acetic acid ethyl ester (30.4 g, 169 mmol) in dimethylformamide (100 ml). After the initial boiling had stopped, the reaction was heated to 100 ° C. for 10 minutes and cooled to room temperature. A solution of 2-chloro-ethyl ester (37.2 g, 169 mmol) in dimethylformamide (5 ml) was added and the reaction was heated to 100 ° C. for 1 hour and cooled to room temperature over 18 hours. The reaction mixture was partitioned between diethylether (300 ml) and water (300 ml), the organic phase removed, washed with water (100 ml), dried over MgSO ₄ and the solvent removed under reduced pressure. The residue was purified by thermal distillation to give [2- (2-chloro-ethoxy) -phenyl] -acetic acid ethyl ester (22.0 g) as a pale yellow oil. Boiling point 170-180 ° C. V _max (thin film) 1735 cm ⁻¹ (C═O, ester); Absence of OH elongation. Found C, 59.35; H, 6.29. C ₁₂ H ₁₅ ClO ₃ is C, 59.38; H, required 6.23%.
[434] Manufacture 41
[435] [2- (2-imidazol-1-yl-ethoxy) -phenyl] -acetic acid
[436]
[437] [2- (2-imidazol-1-yl-ethoxy) -phenyl] -acetic acid ethyl ester (3.5 g, 113 mmol) was stirred at 100 ° C. for 6 h in 50% aqueous hydrochloric acid (20 ml). After cooling to room temperature, the solvent was removed under reduced pressure and the residue was recrystallized from isopropyl alcohol to give [2- (2-imidazol-1-yl-ethoxy) -phenyl] -acetic acid (2.73 g) as white Obtained as a solid. Melting point 146-147 ° C. V _max (thin film) 3410 (OH), 1722 cm ⁻¹ (C═O, acid). Found C, 54.89; H, 5, 25; N, 9.80. C ₁₃ H ₁₄ N ₂ 0 ₃ · 1 mol HCl is C, 55.22; H, 5. 35; N, required 9.91%.
[438] Manufacture 42
[439] 5-cyclopentyl-4- [2- (2-trifluoromethoxy-phenyl) -acetylamino] -1 H-pyrazole-3-carboxylic acid amide
[440]
[441] Carbonyldiimidazole (84 mg, 0.515 mmol) is added to a solution of 2-trifluoromethoxy-phenyl-acetic acid (113 mg, 0.515 mmol) in tetrahydrofuran (4 ml) at room temperature under nitrogen and the mixture is 3 Stir for hours. 4-amino-5-cyclopentyl-1H-pyrazole-3-carboxylic acid amide (100 mg, 0.515 mmol) was added and the reaction stirred for 18 hours. The reaction mixture was diluted with water (20 ml), acidified to pH 2 with 2N HCl and extracted with ethyl acetate (2 × 20 ml). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure to afford 5-cyclopentyl-4- [2- (2-trifluoromethoxy-phenyl) -acetylamino] -1 H-pyrazole-3-carboxylic acid Amide (120 mg) was obtained as an off-white solid. LRMS (electrospray): m / z [M + H] ⁺ 397, [MH] ⁺ 395.
[442] Manufacture 43
[443] 5-Isobutyl-4- [2- (2-trifluoromethoxy-phenyl) -acetylamino] -1 H-pyrazole-3-carboxylic acid amide
[444]
[445] Carbonyldiimidazole (84 mg, 0.515 mmol) is added to a solution of 2-trifluoromethoxy-phenyl-acetic acid (113 mg, 0.515 mmol) in tetrahydrofuran (4 ml) at room temperature under nitrogen and the mixture is 3 Stir for hours. 4-amino-5-isobutyl-1H-pyrazole-3-carboxylic acid amide (100 mg, 0.515 mmol) was added and the reaction stirred for 18 hours. The reaction mixture was diluted with water (20 ml), acidified to pH 2 with 2N HCl and extracted with ethyl acetate (2 × 20 ml). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure to afford 5-isobutyl-4- [2- (2-trifluoromethoxy-phenyl) -acetylamino] -1H-pyrazole-3-carboxylic acid Amide (142 mg) was obtained as an off-white solid. LRMS (electrospray): m / z [M + H] ⁺ 385, [MH] ⁺ 383.
[446] Manufacture 44
[447] 5-Pyridin-3-yl-4- [2- (2-trifluoromethoxy-phenyl) -acetylamino] -1 H-pyrazole-3-carboxylic acid amide
[448]
[449] Carbonyldiimidazole (144 mg, 0.886 mmol) is added to a solution of 2-trifluoromethoxy-phenyl-acetic acid (195 mg, 0.886 mmol) in tetrahydrofuran (5 ml) at room temperature under nitrogen and the mixture is 1 Stir for hours. 4-amino-5-cyclopropyl-1H-pyrazole-3-carboxylic acid amide (180 mg, 0.886 mmol) was added and the reaction stirred for 18 hours. The reaction mixture was diluted with brine (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure to afford 5-pyridin-3-yl-4- [2- (2-trifluoromethoxy-phenyl) -acetylamino] -1 H-pyrazole-3- Carboxylic acid amide (345 mg) was obtained as an off-white solid. LRMS (electrospray): m / z [M + Na] ⁺ 428, [MH] ⁺ 404.

权利要求:
Claims (15)
[1" claim-type="Currently amended] A method of treating insulin resistance syndrome in a mammal comprising administering to the mammal a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug, solvate or salt.
[2" claim-type="Currently amended] The method of claim 1, wherein the cGMP PDE9 inhibitor is a compound of formula (I): a pharmaceutically acceptable salt, solvate or prodrug thereof.
<Formula I>

Where
R ¹ is H or (C ₁ -C ₆ ) alkyl;
R ² is straight or branched chain (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl or heteroaryl;
R ³ is substituted by 1 to 2 groups independently selected from Ar, (C ₃ -C ₇ ) cycloalkyl, OAr, SAr, NC (O) (C ₁ -C ₆ ) alkyl, heteroaryl, xanthene and naphthalene Linear or branched (C ₁ -C ₆ ) alkyl which may be;
Ar is a group of the formula:

Wherein R ⁴ , R ⁵ and R ⁶ are H, halo, phenoxy, phenyl, CF ₃ , OCF ₃ , S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, O (C Independently selected from ₁ -C ₆ ) alkyl, said alkyl may be substituted by 1 to 3 groups selected from a heteroaryl group or a phenyl group (phenyl group is selected from halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl Or R ⁴ and R ⁵ together may form a (C ₂ -C ₃ ) alkyl linking group which may comprise a heteroatom selected from O, S and N)
Heteroaryl is a 5-6 membered aromatic heterocycle containing 1-3 heteroatoms independently selected from O, S and N, said heterocycle being (C ₁ -C ₆ ) alkyl, halo and phenyl (phenyl May be substituted by 1 to 3 substituents independently selected from halo and 1 to 3 groups selected from (C ₁ -C ₆ ) alkyl; Provided that when R ¹ is -CH ₃ , R ² cannot be -CH ₂ CH ₂ CH ₃ .
[3" claim-type="Currently amended] The compound of claim 2, wherein R ¹ is H or CH ₃ ; R ² is (C ₃ -C ₄ ) alkyl, cyclopentyl or pyridinyl; R ³ is (C ₁ -C ₃ ) alkyl which may be substituted by 1 to 2 groups selected from Ar, (C ₃ -C ₇ ) cycloalkyl and heteroaryl; R ⁴ , R ⁵ and R ⁶ are H, halo, phenoxy, phenyl, CF ₃ , OCF ₃ , S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, O (C ₁ -C ₆ Each independently selected from alkyl; Alkyl in the definition of R ⁴ , R ⁵ and R ⁶ is a heteroaryl group or a phenyl group which may be substituted by one to three groups selected from halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl. May be substituted; R ⁴ and R ⁵ together may form a C ₂ alkyl linking group which may comprise an O atom; Heteroaryl is a 5-6 membered aromatic heterocycle containing two or more nitrogen atoms, said heterocycle being selected from (C ₁ -C ₆ ) alkyl, halo and phenyl (phenyl from halo and (C ₁ -C ₆ ) alkyl Optionally substituted with 1 to 3 substituents independently.
[4" claim-type="Currently amended] The method of claim 1, wherein the mammal is treated with 5- (3-chloro-benzyl) -3-isopropyl-1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one Administering a drug, or a pharmaceutically acceptable salt of said compound or prodrug.
[5" claim-type="Currently amended] A method of treating type 2 diabetes in a mammal comprising administering to the mammal a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug, solvate or salt.
[6" claim-type="Currently amended] The method of claim 5, wherein the cGMP PDE9 inhibitor is a compound of formula (I): a pharmaceutically acceptable salt, solvate or prodrug thereof.
<Formula I>

Where
R ¹ is H or (C ₁ -C ₆ ) alkyl;
R ² is straight or branched chain (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl or heteroaryl;
R ³ is substituted by 1 to 2 groups independently selected from Ar, (C ₃ -C ₇ ) cycloalkyl, OAr, SAr, NC (O) (C ₁ -C ₆ ) alkyl, heteroaryl, xanthene and naphthalene Linear or branched (C ₁ -C ₆ ) alkyl which may be;
Ar is a group of the formula:

Wherein R ⁴ , R ⁵ and R ⁶ are H, halo, phenoxy, phenyl, CF ₃ , OCF ₃ , S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, O (C Independently selected from ₁ -C ₆ ) alkyl, said alkyl may be substituted by 1 to 3 groups selected from a heteroaryl group or a phenyl group (phenyl group is selected from halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl Or R ⁴ and R ⁵ together may form a (C ₂ -C ₃ ) alkyl linking group which may comprise a heteroatom selected from O, S and N)
Heteroaryl is a 5-6 membered aromatic heterocycle containing 1-3 heteroatoms independently selected from O, S and N, said heterocycle being (C ₁ -C ₆ ) alkyl, halo and phenyl (phenyl May be substituted by 1 to 3 substituents independently selected from halo and 1 to 3 groups selected from (C ₁ -C ₆ ) alkyl; Provided that when R ¹ is -CH ₃ , R ² cannot be -CH ₂ CH ₂ CH ₃ .
[7" claim-type="Currently amended] The compound of claim 6, wherein R ¹ is H or CH ₃ ; R ² is (C ₃ -C ₄ ) alkyl, cyclopentyl or pyridinyl; R ³ is (C ₁ -C ₃ ) alkyl which may be substituted by 1 to 2 groups selected from Ar, (C ₃ -C ₇ ) cycloalkyl and heteroaryl; R ⁴ , R ⁵ and R ⁶ are H, halo, phenoxy, phenyl, CF ₃ , OCF ₃ , S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, O (C ₁ -C ₆ Each independently selected from alkyl; Alkyl in the definition of R ⁴ , R ⁵ and R ⁶ is a heteroaryl group or a phenyl group which may be substituted by one to three groups selected from halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl. May be substituted; R ⁴ and R ⁵ together may form a C ₂ alkyl linking group which may comprise an O atom; Heteroaryl is a 5-6 membered aromatic heterocycle containing two or more nitrogen atoms, said heterocycle being selected from (C ₁ -C ₆ ) alkyl, halo and phenyl (phenyl from halo and (C ₁ -C ₆ ) alkyl Optionally substituted with 1 to 3 substituents independently.
[8" claim-type="Currently amended] 6. The method of claim 5, wherein the mammal is treated with 5- (3-chloro-benzyl) -3-isopropyl-1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one, Administering a drug, or a pharmaceutically acceptable salt of said compound or prodrug.
[9" claim-type="Currently amended] Dyslipidemia in said mammal comprising administering to said mammal a cGMP PDE9 inhibitor, prodrug or solvate thereof, or a pharmaceutically acceptable salt of said PDE9 inhibitor, prodrug, solvate or salt Method of treatment.
[10" claim-type="Currently amended] 10. The method of claim 9, wherein the cGMP PDE9 inhibitor is a compound of formula (I): a pharmaceutically acceptable salt, solvate or prodrug thereof.
<Formula I>

Where
R ¹ is H or (C ₁ -C ₆ ) alkyl;
R ² is straight or branched chain (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl or heteroaryl;
R ³ is substituted by 1 to 2 groups independently selected from Ar, (C ₃ -C ₇ ) cycloalkyl, OAr, SAr, NC (O) (C ₁ -C ₆ ) alkyl, heteroaryl, xanthene and naphthalene Linear or branched (C ₁ -C ₆ ) alkyl which may be;
Ar is a group of the formula:

Wherein R ⁴ , R ⁵ and R ⁶ are H, halo, phenoxy, phenyl, CF ₃ , OCF ₃ , S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, O (C Independently selected from ₁ -C ₆ ) alkyl, said alkyl may be substituted by 1 to 3 groups selected from a heteroaryl group or a phenyl group (phenyl group is selected from halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl Or R ⁴ and R ⁵ together may form a (C ₂ -C ₃ ) alkyl linking group which may comprise a heteroatom selected from O, S and N)
Heteroaryl is a 5-6 membered aromatic heterocycle containing 1-3 heteroatoms independently selected from O, S and N, said heterocycle being (C ₁ -C ₆ ) alkyl, halo and phenyl (phenyl May be substituted by 1 to 3 substituents independently selected from halo and 1 to 3 groups selected from (C ₁ -C ₆ ) alkyl; Provided that when R ¹ is -CH ₃ , R ² cannot be -CH ₂ CH ₂ CH ₃ .
[11" claim-type="Currently amended] Protein kinase inhibitors, AMP-activated protein kinases, weight loss agents, insulin, PPAR-γ agonists, PPAR-γ antagonists, PPAR-α agonists, dual PPAR-γ / PPAR-α agonists, sorbitol dehydrogenase inhibitors, glycogen phospho A combination comprising at least one of a rilaase inhibitor, biguanide, HMG-CoA reductase inhibitor, aldose reductase inhibitor or PDE5 inhibitor and a cGMP PDE9 inhibitor.
[12" claim-type="Currently amended] The combination of claim 11, wherein the cGMP PDE9 inhibitor is a compound of formula (I): a pharmaceutically acceptable salt, solvate or prodrug thereof.
<Formula I>

Where
R ¹ is H or (C ₁ -C ₆ ) alkyl;
R ² is straight or branched chain (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl or heteroaryl;
R ³ is substituted by 1 to 2 groups independently selected from Ar, (C ₃ -C ₇ ) cycloalkyl, OAr, SAr, NC (O) (C ₁ -C ₆ ) alkyl, heteroaryl, xanthene and naphthalene Linear or branched (C ₁ -C ₆ ) alkyl which may be;
Ar is a group of the formula:

Wherein R ⁴ , R ⁵ and R ⁶ are H, halo, phenoxy, phenyl, CF ₃ , OCF ₃ , S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, O (C Independently selected from ₁ -C ₆ ) alkyl, said alkyl may be substituted by 1 to 3 groups selected from a heteroaryl group or a phenyl group (phenyl group is selected from halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl Or R ⁴ and R ⁵ together may form a (C ₂ -C ₃ ) alkyl linking group which may comprise a heteroatom selected from O, S and N)
Heteroaryl is a 5-6 membered aromatic heterocycle containing 1-3 heteroatoms independently selected from O, S and N, said heterocycle being (C ₁ -C ₆ ) alkyl, halo and phenyl (phenyl May be substituted by 1 to 3 substituents independently selected from halo and 1 to 3 groups selected from (C ₁ -C ₆ ) alkyl; Provided that when R ¹ is -CH ₃ , R ² cannot be -CH ₂ CH ₂ CH ₃ .
[13" claim-type="Currently amended] The compound of claim 12, wherein R ¹ is H or CH ₃ ; R ² is (C ₃ -C ₄ ) alkyl, cyclopentyl or pyridinyl; R ³ is (C ₁ -C ₃ ) alkyl which may be substituted by 1 to 2 groups selected from Ar, (C ₃ -C ₇ ) cycloalkyl and heteroaryl; R ⁴ , R ⁵ and R ⁶ are H, halo, phenoxy, phenyl, CF ₃ , OCF ₃ , S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, O (C ₁ -C ₆ Each independently selected from alkyl; Alkyl in the definition of R ⁴ , R ⁵ and R ⁶ is a heteroaryl group or a phenyl group which may be substituted by one to three groups selected from halo, CF ₃ , OCF ₃ and (C ₁ -C ₆ ) alkyl. May be substituted; R ⁴ and R ⁵ together may form a C ₂ alkyl linking group which may comprise an O atom; Heteroaryl is a 5-6 membered aromatic heterocycle containing two or more nitrogen atoms, said heterocycle being selected from (C ₁ -C ₆ ) alkyl, halo and phenyl (phenyl from halo and (C ₁ -C ₆ ) alkyl Combinations which may be substituted by one to three substituents independently selected from &lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt;
[14" claim-type="Currently amended] The method of claim 13, wherein the cGMP PDE9 inhibitor is 5- (3-chloro-benzyl) -3-isopropyl-1,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-one, A combination comprising a prodrug or a pharmaceutically acceptable salt of the compound or prodrug and comprising a pharmaceutically acceptable vehicle, carrier or diluent.
[15" claim-type="Currently amended] a) a first unit dosage form comprising a cGMP PDE9 inhibitor, a prodrug or solvate thereof, or a pharmaceutically acceptable salt of said compound, prodrug or solvate and a pharmaceutically acceptable vehicle, carrier or diluent;
b) protein kinase inhibitors; AMP-activated protein kinases; Weight loss agents; insulin; PPAR-γ agonists; PPAR-γ antagonists; PPAR-α agonists; Dual PPAR-γ / PPAR-α agonists; Sorbitol dehydrogenase inhibitors; Glycogen phosphorylase inhibitors; Biguanides; HMG-CoA reductase inhibitors; Aldose reductase inhibitors; Or PDE5 inhibitors; The protein kinase inhibitor, AMP-activated protein kinase, weight loss agent, insulin, PPAR-γ agonist, PPAR-γ antagonist, PPAR-α agonist, dual PPAR-γ / PPAR-α agonist, sorbitol dehydrogenase inhibitor, glycogen force Prodrugs or solvates of forillase inhibitors, biguanides, vastatin, aldose reductase inhibitors or PDE5 inhibitors; Or pharmaceutical of the compound, prodrug or solvate
A second unit dosage form comprising an acceptable salt and a pharmaceutically acceptable vehicle, carrier or diluent; And
c) containers
Kit comprising a.

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同族专利:

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公开号 | 公开日

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ZA200402173B|2005-03-18|

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JP2005508978A|2005-04-07|

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MXPA04004170A|2004-09-06|

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US6967204B2|2005-11-22|

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IL161155D0|2004-08-31|

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BR0213817A|2004-10-19|

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US20040023989A1|2004-02-05|

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CN1575191A|2005-02-02|

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EP1444009A1|2004-08-11|

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WO2003037432A1|2003-05-08|

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HU0401998A2|2005-01-28|

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US20050070557A1|2005-03-31|

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CA2465632A1|2003-05-08|

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PL370599A1|2005-05-30|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-11-02|Priority to US33698101P

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2001-11-02|Priority to US60/336,981

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2002-09-12|Application filed by 화이자 프로덕츠 인크.

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2002-09-12|Priority to PCT/IB2002/003754

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2004-06-23|Publication of KR20040053210A

优先权:

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申请号 | 申请日 | 专利标题

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US33698101P| true| 2001-11-02|2001-11-02|

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US60/336,981|2001-11-02|

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PCT/IB2002/003754|WO2003037432A1|2001-11-02|2002-09-12|Treatment of insulin resistance syndrome and type 2 diabetes with pde9 inhibitors|