A compound having the structureuseful for treating hypertension, Pulmonary Arterial Hypertension (PAH), congestive heart failure, conditions resulting from excessive water retention, cardiovascular disease, diabetes, oxidative stress, endothelial dysfunction, cirrhosis, pre-eclampsia, osteoporosis or nephropathy.

BACKGROUND OF THE INVENTION

WO09103875 describes diazeniumdiolate dihydro indole derivatives of a specified formula for treating hypertension and cardiovascular disease. WO07144512 describes diazeniumdiolate tetrazole-biphenyl derivatives of a specified formula for treating hypertension and cardiovascular disease. US 2005137191 describes nitrate ester compounds, e.g., 1,2-dichloro-4-(2-methyl-butyldisulfanyl)-benzene, useful for preventing or mitigating tissue and/or cellular damage associated with aging, septic shock, ulcers, gastritis, ulcerative colitis and Crohn's disease. US 2005065194 describes use of an endothelial gene differentiation receptor modulator such as 1-(2-ethoxyphenyl)-3-(hydroxyphenylamino)-pyrrolidine-2,5-dione, to modulate receptor-mediated biological activity such as cell proliferation stimulated by lysophosphatidic acid leading to ovarian cancer and other forms of cancer, and to treat conditions such as cancer, cardiovascular disease, ischemia, and atherosclerosis. WO 9746521 describes aliphatic nitrate esters useful for treating neurological conditions, especially Parkinson's, Alzheimer's and Huntington's disease.

The present invention relates to novel diazeniumdiolate heterocyclic derivatives, useful as antihypertensive agents.

SUMMARY OF THE INVENTION

The present invention includes diazeniumdiolate heterocyclic derivatives, including various pharmaceutically acceptable salts and hydrates of these forms, and pharmaceutical formulations comprising the diazeniumdiolate heterocyclic derivatives.

The invention also includes a method for treating hypertension, Pulmonary Arterial Hypertension (PAH), congestive heart failure, conditions resulting from excessive water retention, cardiovascular disease, diabetes, oxidative stress, endothelial dysfunction, cirrhosis, pre-eclampsia, osteoporosis or nephropathy, comprising administering a compounds of the invention to a patient having such a condition, or being at risk to having such condition.

The invention is a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein
X is O or NR7;

is attached to any ring carbon atom other than the carbon to which R1and R2are attached;
R1is hydrogen, —C(O)OC1-6alkyl, or —C(O)OH, or together with R2, forms ═O;
R2is hydrogen, or together with R1, forms ═O;
R4is

—C1-6alkylene-aryl, or

R5and R6, which are attached to any available carbon ring atom, are independently

hydrogen,deuterium,—C1-6alkyl,—C(O)OC1-6alkyl,—C(O)OH,aryl,or R5and R6, when they are attached to the same carbon atom, together form ═O;R7ishydrogen,—C1-6alkyl,—C1-6alkylene-aryl,—C1-6alkylene C(O)O—C1-6alkyl,—C1-6alkylene-CR8R9R10,—CN,—C(O)O—C1-6alkyl,—C(O)O—C1-6alkylene CR8R9R10,—C(O)C1-6alkyl,—C(O)OC3-6carbocycle,—C(O)CHF2,—C(O)CF3,—C(O)CH2OH,—C(O)aryl,—C(O)heteroaryl, wherein heteroaryl is an unsaturated 5- or 6-membered ring having 1-4 heteroatoms selected from N, O and S,—C(O)C1-6alkyleneOH,—C(O)C3-6carbocycle,—C(O)NH2,—C(O)NHC1-6alkyl,—C(O)NH-adamantyl,—C(O)heterocycle, wherein heterocycle is a saturated monocyclic 5- to 8-membered ring having 1-4 heteroatoms selected from N, O and S, or a 7- to 12-membered saturated bicyclic ring system having 1-6 heteroatoms selected from N, O and S,—C(O)NHC3-6carbocycle,—C(O)N(C1-6alkyl)C1-6alkyl,—C(O)NHSO2aryl,—SOC1-6alkyl,—SO2C1-6alkyl,—SO2NH(C1-6alkyl),—SO2N(C1-6alkyl)(C1-6alkyl),—SO2CF3,—SO2aryl,—SO2heteroaryl, wherein heteroaryl is an unsaturated 5- or 6-membered ring having 1-4 heteroatoms selected from N, O and S,aryl,an unsaturated 5- or 6-membered heteroaryl ring having 1-4 heteroatoms selected from N, O and S, or—C3-6carbocycle;wherein aryl, alkyl, alkylene, carbocycle, heteroaryl, and heterocycle are unsubstituted or substituted with 1-4 groups independently selected from —CN, halogen, —CF3, —OCF3, —C(O)NH2, —C1-6alkyl, —C3-6carbocycle, ═O, —C(O)OC1-6alky, —COOH, —C(CH3)2OH, —SO2(C1-6alkyl), aryl, an unsaturated 5-membered heteroaryl ring having 1-3 nitrogen atoms, or —OC1-6alkyl,wherein R8and R9, together with the carbon to which they are attached, form a C3-6carbocycle or 4-8-membered heterocycle, andwherein R10is C1-6alkyl;
and pharmaceutically acceptable salts thereof.

In one embodiment, the compound is of the formula which is

In another embodiment, the compound is of the formula which is

In another embodiment, the compound is of the formula which is

In another embodiment, X is —NR7and R7is —C1-6alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2-CF3.

In another embodiment, X is —NR7and R7is —SO2C1-6alkyl.

In another embodiment, X is —NR7and R7is aryl, wherein aryl is unsubstituted or substituted with 1-2 groups independently selected from —CN, —CF3, —OCF3, —CH3or an unsaturated 5-membered heteroaryl ring having 3 nitrogen atoms.

In another embodiment, X is —NR7and R7is an unsaturated heteroaryl 6-membered ring having 1-2 nitrogen atoms, wherein heteroaryl is unsubstituted or substituted with 1-4 groups independently selected from Cl, an unsaturated 5-membered heteroaryl ring having 3 nitrogen atoms, —CN, —CF3, and —C(O)NH2.

In a class of this embodiment, X is —NR7and R7is

In another embodiment, R1and R2, together with the atom to which they are attached, form ═O, and R5and R6are hydrogen.

In another embodiment, X is —NR7and R7is—C1-6alkyl,—C1-6alkylene-aryl,—C1-6alkyleneC(O)O—C1-6alkyl,—C1-6alkylene-CR8R9R10,—CN,—C(O)O—C1-6alkyl,—C(O)O—C1-6alkylene CR8R9R10,—C(O)C1-6alkyl,—C(O)OC3-6carbocycle,—C(O)CHF2,—C(O)CF3,—C(O)CH2OH,—C(O)aryl,—C(O)heteroaryl, wherein heteroaryl is an unsaturated 5- or 6-membered ring having 1-4 heteroatoms selected from N, O and S,—C(O)C1-6alkyleneOH,—C(O)C3-6carbocycle,—C(O)NH2,—C(O)NHC1-6alkyl,—C(O)NH-adamantyl,—C(O)heterocycle, wherein heterocycle is a saturated monocyclic 5- to 8-membered ring having 1-4 heteroatoms selected from N, O and S, or a 7- to 12-membered saturated bicyclic ring system having 1-6 heteroatoms selected from N, O and S,—C(O)NHC3-6carbocycle,—C(O)N(C1-6alkyl)C1-6alkyl,—C(O)NHSO2aryl,—SOC1-6alkyl,—SO2C1-6alkyl,—SO2NH(C1-6alkyl),—SO2N(C1-6alkyl)(C1-6alkyl),—SO2CF3,—SO2aryl,—SO2heteroaryl, wherein heteroaryl is an unsaturated 5- or 6-membered ring having 1-4 heteroatoms selected from N, O and S,aryl,an unsaturated 5- or 6-membered heteroaryl ring having 1-4 heteroatoms selected from N, O and S, or—C3-6carbocycle;wherein aryl, alkyl, alkylene, carbocycle, heteroaryl, and heterocycle are unsubstituted or substituted with 1-4 groups independently selected from —CN, halogen, —CF3, —OCF3, —C(O)NH2, —C1-6alkyl, —C3-6carbocycle, ═O, —C(O)OC1-6alky, —COOH, —C(CH3)2OH, —SO2(C1-6alkyl), aryl, an unsaturated 5-membered heteroaryl ring having 1-3 nitrogen atoms, or —OC1-6alkyl,wherein R8and R9, together with the carbon to which they are attached, form a C3-6carbocycle or 4-8-membered heterocycle, andwherein R10is C1-6alkyl.

In another embodiment, compounds of the invention areO2-[1-(tert-butoxycarbonyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[(cyclohexyloxy)carbonyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[(propan-2-yloxy)carbonyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[(2,2-dimethylpropoxy)carbonyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[(cyclopropylmethoxy)carbonyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-{[(3-methyloxetan-3-yl)methoxy]carbonyl}pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(tert-butylcarbamoyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(tricyclo[3.3.1.13,7]dec-1-ylcarbamoyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[(2-phenylpropan-2-yl)carbamoyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[(1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,(±)—O2-[1-(tert-butylcarbamoyl)azepan-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-(1-acetylpiperidin-4-yl)1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{1-[(4-cyanophenyl)carbonyl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{1-[(2-methylphenyl)carbonyl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,(±)—O2-[1-(pyridin-4-ylcarbonyl)azepan-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(methylsulfonyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(tert-butylsulfonyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(4-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(3-cyanophenyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(5-cyanopyrazin-2-yl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(3-cyanophenyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(6-cyanopyridin-2-yl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[3-(trifluoromethyl)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(5-chloropyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(5-carbamoylpyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[3-(1H-1,2,3-triazol-1-yl)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{1-[3-(1H-1,2,4-triazol-1-yl)phenyl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{1-[3-(1H-1,2,3-triazol-1-yl)phenyl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{1-[5-(1H-1,2,3-triazol-1-yl)pyridin-2-yl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-(tetrahydro-2H-pyran-4-yl)1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(3-methylphenyl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-2-oxo-1-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(5-chloropyridin-3-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(5-cyanopyridin-2-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate, orO2-{(3R)-2-oxo-1-[4-(trifluoromethyl)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,or a pharmaceutically acceptable salt thereof.

In another embodiment, compounds of the invention areO2-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(4-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-1-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(6-cyanopyridin-2-yl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(5-chloropyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[1-(5-carbamoylpyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(5-chloropyridin-3-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-[(3R)-1-(5-cyanopyridin-2-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,O2-{(3R)-2-oxo-1-[4-(trifluoromethyl)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,or a pharmaceutically acceptable salt thereof.

Compounds of the invention can be used to treat hypertension, treat angina, improve insulin sensitivity, and provide renal protection. The compounds can be used alone or in combination (e.g., separate but co-administered, or administered in a fixed dose) with other antihypertensives such as, for example, angiotensin II receptor blockers, diuretics, ACE inhibitors, (3-blockers, and calcium channel blockers.

Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Additional specific cationic salts include tromethamine, benzathine, benethamine, diethylammonium, epolamine, hydrabamine.

When the compounds of the invention contain one chiral center, the term “stereoisomer” includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as the racemic mixture. The compounds of the present invention may have multiple chiral centers, providing for multiple stereoisomers. This invention includes all of the stereoisomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, all possible stereoisomers are included. Where used, the structure marking “*” indicates the location of a carbon atom that is a chiral center. When bonds to a chiral carbon are depicted as straight lines, it is understood that both (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are represented.

Some of the compounds described herein may exist as tautomers. The individual tautomers as well as mixtures thereof are encompassed with the described compounds.

As used herein except where noted, “alkyl” is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g. methyl may be represented by conventional abbreviations including “Me” or CH3or a symbol that is an extended bond as the terminal group, e.g. “”, ethyl may be represented by “Et” or CH2CH3, propyl may be represented by “Pr” or CH2CH2CH3, butyl may be represented by “Bu” or CH2CH2CH2CH3, etc. “C1-4alkyl” (or “C1-C4alkyl”) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. C1-4alkyl includes n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is specified, 1-4 carbon atoms are intended for linear or branched alkyl groups.

The term “alkylene” refers to any divalent linear or branched chain aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, “—C1-C6alkylene-” refers to any of the C1to C6linear or branched alkylenes, and “—C1-C4alkylene-” refers to any of the C1to C4linear or branched alkylenes. A class of alkylenes of particular interest with respect to the invention is —(CH2)1-6—, and sub-classes of particular interest include —(CH2)1-4—, —(CH2)1-3—, —(CH2)1-2—, and —CH2—. Another sub-class of interest is an alkylene selected from the group consisting of —CH2—, —CH(CH3)—, and —C(CH3)2—. Expressions such as “C1-C4alkylene-phenyl” and “C1-C4alkyl substituted with phenyl” have the same meaning and are used interchangeably.

The term “aryl”, alone or in combination, relates to a phenyl, naphthyl or indanyl group, preferably a phenyl group. The abbreviation “Ph” represents phenyl.

The term “carbocycle” (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to a C3to C8monocyclic saturated or unsaturated ring. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound. Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.

The term “heteroaryl” refers to an unsaturated ring having a specified number of atom members (e.g., 5 or 6-membered), including a specified number of heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms independently selected from N, O or S), e.g., 5-membered rings containing one nitrogen (pyrrole), one oxygen (furan) or one sulfur (thiophene) atom, 5-membered rings containing one nitrogen and one sulfur (thiazole) atom, 5-membered rings containing one nitrogen and one oxygen (oxazole or isoxazole) atom, 5-membered rings containing two nitrogen (imidazole or pyrazole) atoms, five-membered aromatic rings containing three nitrogen atoms, five-membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom, five-membered aromatic rings containing two heteroatoms independently selected from oxygen, nitrogen and sulfur, 6-membered rings containing one nitrogen (pyridine), or one oxygen (pyran) atom, 6-membered rings containing two nitrogen (pyrazine, pyrimidine, or pyridazine) atoms, 6-membered rings containing three nitrogen (triazine) atoms, a tetrazolyl ring; a thiazinyl ring; or coumarinyl. Examples of such ring systems are furanyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, imidazolyl, triazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, and isoxazolyl.

The compounds of the invention are useful for treating hypertension, Pulmonary Arterial Hypertension, congestive heart failure, angina, conditions resulting from excessive water retention, cardiovascular diseases, diabetes, oxidative stress, endothelial dysfunction, cirrhosis, pre-eclampsia, osteoporosis, or nephropathy, comprising administering a compounds of the invention to a patient having such a condition, or being at risk to having such condition

The invention also relates to the use of compounds of the invention for the preparation of a medicament for the treatment and/or prophylaxis of the above-mentioned diseases.

Oral dosages of the compounds of the invention, when used for the indicated effects, will range between about 0.0125 mg per kg of body weight per day (mg/kg/day) to about 7.5 mg/kg/day, preferably 0.0125 mg/kg/day to 3.75 mg/kg/day, and more preferably 0.3125 mg/kg/day to 1.875 mg/kg/day. For example, an 80 kg patient would receive between about 1 mg/day and 600 mg/day, preferably 1 mg/day to 300 mg/day, more preferably 5 mg/day to 150 mg/day, and more preferably 5 mg/day to 100 mg/day. A suitably prepared medicament for once a day administration would thus contain between 1 mg and 600 mg, preferably between 1 mg and 300 mg, and more preferably between 25 mg and 300 mg, e.g., 25 mg, 50 mg, 100 mg, 150, 200, 250 and 300 mg. Advantageously, the compound of the invention may be administered in divided doses of two, three, or four times daily. For administration twice a day, a suitably prepared medicament would contain between 0.5 mg and 300 mg, preferably between 0.5 mg and 150 mg, more preferably between 12.5 mg and 150 mg, e.g., 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg and 150 mg.

The compounds of the invention can be administered in such oral forms as tablets, capsules and granules. The compounds of the invention are typically administered as active ingredients in admixture with suitable pharmaceutical binders as described below. % w/w expresses the weight percent of the indicated composition constituent compared to the total composition. Suitable fillers used in these dosage forms include microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, lactose, mannitol, and starch, preferably microcrystalline cellulose, dicalcium phosphate, lactose or mixtures thereof. Suitable binders include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, and polyvinyl pyrrolidone. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, sodium stearyl fumarate, stearic acid and the like, preferably magnesium stearate. Suitable coating compositions include aqueous dispersion or organic solution of insoluble polymers such as ethyl cellulose, cellulose acetate, cellulose acetate butyrate and acrylate copolymers commercially known as Eudragit®. Plasticizers include triethyl citrate, dibutyl sebacate, dibutyl phthalate, triacetin and castor oil. Antitacking agents include talc, kaolin, colloidal silica or mixtures thereof.

Methods of Synthesis

Several methods for preparing the compounds of this invention are described in the following Schemes and Examples. Starting materials and intermediates are made from known procedures or as otherwise illustrated. R11is nitrogen protecting group such as —CH2CH═CHR where R is, for example, hydrogen, C1-6alkyl, e.g., —C(CH3)3, aryl, and CH2aryl. M is an atom or groups that can be the counterion of the diazeniumdiolate salt, such as lithium, sodium, potassium, rubidium, cesium, magnesium, calcium, strontium, barium, or ammonium R13R14R15R16N+where R13-R16is hydrogen or C1-6alkyl. R12is, for example, methyl, CF3or substituted phenyl. X is Cl or —OSO2R12.

Scheme 1 describes a convenient method to prepare the alkali metal diazeniumdiolates of the general structure 1-2 in this invention. The allyl amine 1-1 is treated with nitric oxide at an appropriate temperature such as room temperature in the presence of a suitable base such as sodium hydroxide, sodium methoxide, sodium tert-butoxide, sodium trimethylsilanolate, or the corresponding potassium bases, in an appropriate solvent such as acetonitrile, methanol, tetrahydrofuran, N,N-dimethylformamide, or water. Examples on the preparation of the sodium diazeniumdiolates can be found from the literature (Chakrapani, H.; Showalter, B. M.; Citro, M. L.; Keefer, L. K.; Saavedra, J. E.Org. Lett.2007, 9, 4551-4554 and WO Patent 2009/094242.

Scheme 2 delineates a method to prepare O2-alkylated diazeniumdiolates of the general structure 2-6 in this invention. tert-Butoxycarbonyl-protected pyrrolidinols of the general structure 2-1 can be activated for displacement at an appropriate temperature such as room temperature with a suitable reagent such as methanesulfonic anhydride, benzenesulfonyl chloride, 4-(trifluoromethyl)phenylsulfonyl chloride in the presence or absence of a base such as N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine, or lutidine in an appropriate solvent such as dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, toluene, N,N-dimethylformamide, or N-methylpyrrolidinone. The resultant sulfonate 2-2 can be displaced by an appropriate alkali metal diazeniumdiolate salt 1-2 at an appropriate temperature such as room temperature in an appropriate solvent such as dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, toluene, dimethoxyethane, N,N-dimethylformamide, or N-methylpyrrolidinone. The stereochemistry at the sulfonate carbon is typically inverted as a result of the displacement. The tert-butoxycarbonyl protective group can then be removed from product 2-3 with an acid such as hydrochloric acid, trifluoroacetic acid, or phosphoric acid to afford functionalized pyrrolidines 2-4. The desired group R7can be coupled to the pyrrolidine 2-4 using the appropriate method. For example, if R7is an aromatic or a heteroaromatic substituent, the appropriate aromatic or heteroaromatic halide can be coupled to 2-4 with the appropriate combination of palladium source, such as palladium(II)acetate, palladium(II) chloride, tris(dibenzylideneacetone) di(palladium), with the appropriate ligand such as triphenylphosphine, tri(tert-butyl)phosphine, tricyclohexylphosphine, racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1,1′-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(diphenylphosphino)propane, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, or an appropriate pallacycle, such as chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II). Alternatively, if R7is an electron-deficient aromatic or heteroaromatic system, the coupling can be performed through nucleophilic aromatic by reacting the appropriate aromatic or heteroaromatic halide with 2-4 in the presence of an appropriate base, such as potassium carbonate, cesium carbonate, triethylamine at an elevated temperature. If R7is an acyl or a sulfonyl group, the corresponding acyl halide or sulfonyl halide can be used. If R7is a carbamoyl group, the corresponding isocyanate can be used. R11is removed as the last step. When R11is an allyl group, the product 2-5 can be deprotected with the appropriate combination of palladium or platinum source, such as palladium(II)acetate, palladium(II) chloride, tris(dibenzylideneacetone)di(palladium), dichloro(1,5-cyclooctadiene)platinum(II), with the appropriate ligand such as triphenylphosphine, tri(tert-butyl)phosphine, tricyclohexylphosphine, racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1,1′-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(diphenylphosphino)propane, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, or an appropriate pallacycle, such as chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), or a heterogeneous palladium or platinum source, such as palladium on carbon, poisoned palladium on calcium carbonate, platinum on carbon, sulfided platinum on carbon, in the presence of an appropriate scavenger, such as N,N′-dimethylbarbituric acid, dimedone, thiosalicyclic acid, or an appropriate hydrogen donor, such as hydrogen gas, formic acid, sodium borohydride, triethylsilane, tributylstannane.

Scheme 3 describes an alternative method to prepare O2-alkylated diazeniumdiolates of the general structure 3-4 in this invention. The steps are similar to those outlined in scheme 2, but the order of execution of those steps is modified. R7can be installed first on the pyrrolidinol, and the products 3-1 can be activated for displacement. The resultant sulfonates 3-2 can be displaced by an appropriate alkali metal diazeniumdiolate salt 1-2 to yield 3-3. R11is removed as the last step. Typical conditions for executing the transformations have been described above.

To a dichloromethane (8 mL) solution of O2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-allylamino)diazen-1-ium-1,2-diolate (1.00 g, 2.92 mmol) at room temperature was added a 4.0 M dioxane solution of hydrochloric acid (1.46 mL, 5.84 mmol). The reaction mixture was stirred for 16 hours and concentrated in vacuo to afford the hydrochloride salt of the title compound. This crude product was used in the subsequent step without further purification. LC-MS: m/z 243.3 (M+H).

To a dichloromethane (100 mL) solution of benzoic acid (4.03 g, 33.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.4 g, 54.0 mmol) was added tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (5.62 g, 30.0 mmol). The reaction mixture was stirred for 6 hours at room temperature, diluted with water (200 mL) and charged with diethyl ether (200 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogencarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound. This crude product was used in the subsequent step without further purification.

To a dichloromethane (5 mL) solution of tert-butyl (3S)-3-[(phenylcarbonyl)oxy]pyrrolidine-1-carboxylate (2.62 g, 9.00 mmol) was added trifluoroacetic acid (5.55 mL, 72.0 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. Concentration of the reaction mixture in vacuo afforded the trifluoroacetate salt of the title compound. This crude product was used in the subsequent step without further purification.

To a benzene (2 mL) solution of cumylamine (1.80 g, 13.3 mmol) and triethylamine (1.86 mL, 13.3 mmol) was added a 20% toluene solution of phosgene (17.5 mL, 33.3 mmol) dropwise. After completion, the reaction mixture was heated to 60° C. for 2 hours. It was then cooled to room temperature, charged with diethyl ether (20 mL), and filtered. Concentration of the filtrate in vacuo afforded the title compound. This crude product was used in the subsequent step without further purification.

To a dichloromethane (10 mL) solution of tert-butyl 4-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)piperidine-1-carboxylate (EXAMPLE 1, STEP A, 1.20 g, 2.93 mmol) was added trifluoroacetic acid (500 μL, 6.73 mmol). The reaction mixture was stirred for 16 hours and concentrated in vacuo to afford the trifluoroacetate salt of the title compound. This crude product was used in the subsequent step without further purification. LC-MS: m/z 309.9 (M+H).

To a tetrahydrofuran (20 mL) solution of the trifluoroacetate salt of piperidin-4-yl 4-(trifluoromethyl)benzenesulfonate (800 mg, 1.97 mmol) at −78° C. was added tert-butylsulfinyl chloride (209 μL, 2.20 mmol). The reaction mixture was stirred for 10 minutes at −78° C. before triethylamine (1.10 mL, 7.88 mmol) was added. It was then stirred for another 2 hours at −78° C. Diethyl ether (50 mL) was added to the reaction mixture, and the combined organic layers were washed with 1 M hydrochloric acid (30 mL), water (30 mL), brine (30 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The resulting oil was dissolved in dichloromethane (20 mL), cooled to 0° C., and m-chloroperbenzoic acid (374 mg, 2.17 mmol) was added to the solution. The ice-bath was removed, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was washed with saturated sodium bicarbonate (40 mL), water (40 mL), brine (40 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound.

Steps A and B: 1-(5-cyanopyridin-2-yl)piperidin-4-yl 4-(trifluoromethyl)benzenesulfonate was prepared following Steps A and B in EXAMPLE 42.

Step C: Preparation of O2-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butyl-N-allylamino)diazen-1-ium-1,2-diolate

The reaction mixture was cooled to 25-30° C. and Solka Flock powdered cellulose (30 g, 100 wt %) was added. The resulting slurry was stirred at room temperature for 10 min and was filtered through Solka Flock powdered cellulose (15 g, 50 wt %), rinsed with 2-methyl-THF (180 mL, 6 vol). Assay desired product O2-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butyl-N-allylamino)diazen-1-ium-1,2-diolate in the combined filtrates was 25.1 g. The reaction mixture was concentrated to 60 mL (2 vol, total volume) at 30-35° C. The resulting solution was cooled to 20° C. and seeded (50 mg of seed). Slurry was formed and the resulting slurry was stirred at 20° C. for 0.5 h. Heptanes (90 mL, 3 vol) was added dropwise over 0.5 h. The resulting slurry was stirred at 20° C. for 1 h, and at 10° C. for 1 h.

Step D: Preparation of O2-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate

To a nitrogen purged 250 mL 3-neck round bottom, equipped with overhead stirrer, thermocouple, and nitrogen inlet was charged O2-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butyl-N-allylamino)diazen-1-ium-1,2-diolate (10.0 g) and sodium borohydride (1.306 g). The flask was purged with nitrogen for 1 h. Degassed ethanol (45 mL) was added and the slurry stirred slowly at 20-22° C.

In a separate 10 mL round bottom flask under nitrogen atmosphere was charged palladium acetate (62 mg) and DPPP (148 mg). The flask was purged with nitrogen for 30 min and degassed ethanol (6.6 mL) added at room temperature. The mixture was stirred for 30 min at room temperature to obtain a yellow homogeneous solution.

The yellow catalyst solution was added, via syringe, to the allyl O2-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate slurry above in one portion. The yellow slurry was aged at 25° C. for 1 hour and then warmed to 40° C. for 4 h. Reaction progress was monitored by HPLC. Reaction was >99.9% complete in 3.5 h at 40 C.

On complete reaction the mixture was cooled to 25° C. and seeded with crystalline O2-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate (5 mg). The mixture was aged at 20° C. for 30 min to give a thick, but stirrable slurry. The slurry was cooled to 5° C. and a solution of acetic acid (4.98 g) in water (100 mL) added over 30 min maintaining 5-10° C.

The slurry was aged at 5-10° C. for 30 min. Tan solids were filtered and washed with 2:1 water/ethanol (20 mL) and air dried (on funnel) for 3 hours. Crude yield was 12.6 g (with water content approx 30% w/w)

Tan solid was dissolved in IPAC (120 mL) at room temperature. SiO2(4 g) was added and the slurry stirred for 30 min at room temperature. The slurry was filtered through SiO2(4 g) over 10 min and the cake washed with IPAC (40 mL). Combined filtrates were assayed. Assay yield at this point was 52.0 mg/mL (161 mL), 8.38 g.

The IPAC solution was recharged to the vessel through an in-line 5 μm filter clarification and concentrated to about 50 mL. The batch was seeded with O2-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate (5 mg) and allowed to stir for 30 min to give slurry. Heptane (50 mL) was added and the slurry solvent switched to >90% heptane at constant volume and 30-40° C. The resultant slurry (IPAC level at 5-10% v/v by HPLC assay) was aged at 20° C. for 30 min. The slurry was filtered and washed with heptane (30 mL), dried in air 1 h and in vacuo at 30° C. overnight to obtain 8.1 g (>99.7A % 210 nm).

Activity

Compounds of the invention were evaluated for blood pressure reduction efficacy using the following canine telemetry protocol described below.

Male beagle dogs (approximately 1-3 years old) with a body weight of between 10 and 16 kg were surgically implanted with DSI radiotelemetry devices (model: TL11M2-D70-PCT). Briefly, under an inhalant anesthesia, isoflurane/oxygen mixture (1-3.5%/to effect), the body of the telemetry device was positioned and secured intra-abdominally. Subsequently, the arterial catheter of the telemetry device was passed subcutaneously to the inguinal area and introduced into the femoral artery and advanced to the level of the descending aorta. The catheter was secured with 2-0 silk ligatures. The muscle and underlying fascia was closed over the catheter using absorbable suture and the skin was closed using non-absorbable suture. The animals were allowed a minimum recovery period of 2 weeks between surgery and the evaluation of test compounds.

Compound evaluation consisted of a 3 day paradigm at a 3 mg/kg dose. On the first day, no compounds were administered during a 24 hour period of baseline data collection. Blood pressure and heart rate data were collected continuously for one minute periods at 10 minute intervals. On the days of compound administration half the animals received test article with the other half receiving the vehicle used for compound formulation. All test materials were administered by oral gavage in a volume of 1 mL/kg. Data are expressed either as raw values (mm Hg or beats per minute) or as the change from baseline (average value for about 12 hours in low activity period prior to dosing). Change is SBP (systolic blood pressure) and PP (pulse pressure) over time is shown below: