WO1998019672A1 - Composes nitroses et nitrosyles inhibiteurs de la phosphodiesterase, compositions comprenant ces composes et utilisations correspondantes - Google Patents

Composes nitroses et nitrosyles inhibiteurs de la phosphodiesterase, compositions comprenant ces composes et utilisations correspondantes Download PDF

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Publication number
WO1998019672A1
WO1998019672A1 PCT/US1997/019870 US9719870W WO9819672A1 WO 1998019672 A1 WO1998019672 A1 WO 1998019672A1 US 9719870 W US9719870 W US 9719870W WO 9819672 A1 WO9819672 A1 WO 9819672A1
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Prior art keywords
compounds
formula
hydrogen
group
acid
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PCT/US1997/019870
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English (en)
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WO1998019672A9 (fr
Inventor
David S. Garvey
Inigo Saenz De Tejada
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Nitromed Inc.
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Priority claimed from US08/740,764 external-priority patent/US5874437A/en
Application filed by Nitromed Inc. filed Critical Nitromed Inc.
Priority to CA002270118A priority Critical patent/CA2270118A1/fr
Priority to PCT/US1997/019870 priority patent/WO1998019672A1/fr
Priority to EP97946871A priority patent/EP0941086A4/fr
Priority to JP52161698A priority patent/JP2001504457A/ja
Priority to AU51962/98A priority patent/AU722480B2/en
Publication of WO1998019672A1 publication Critical patent/WO1998019672A1/fr
Publication of WO1998019672A9 publication Critical patent/WO1998019672A9/fr
Priority to US09/241,281 priority patent/US6133272A/en
Priority to US09/247,292 priority patent/US6221881B1/en
Priority to US09/247,323 priority patent/US6316457B1/en
Priority to US09/247,295 priority patent/US6197782B1/en
Priority to US09/247,322 priority patent/US6172068B1/en
Priority to US09/247,296 priority patent/US6172060B1/en
Priority to US09/247,320 priority patent/US6197778B1/en
Priority to US09/247,321 priority patent/US6177428B1/en
Priority to US09/247,293 priority patent/US6232321B1/en
Priority to US09/347,426 priority patent/US6211179B1/en
Priority to US09/354,424 priority patent/US6472425B1/en
Priority to US09/387,727 priority patent/US6331543B1/en
Priority to US09/465,965 priority patent/USRE37234E1/en
Priority to US09/941,691 priority patent/US6462044B2/en
Priority to US10/216,886 priority patent/US6930113B2/en
Priority to US10/694,183 priority patent/US20040087591A1/en
Priority to US11/819,514 priority patent/US20080009498A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention generally relates to pharmaceuticals and more specifically to a method and compositions for inducing penile erections in human males suffering from impotence, a method and compositions for treating female sexual dysfunction, and a method and compositions for treating human anal disease resulting from excessive anal sphincter tone.
  • erectile dysfunction is a widespread disorder that is thought to affect about ten to fifteen percent of the adult men.
  • female sexual dysfunction is also a significant problem among adult women.
  • causes of these insufficiencies in addition to anatomical deficiencies of the penis that preclude an erection sufficient for vaginal penetration, have been identified.
  • causes of erectile dysfunction can be categorized as psychogenic, neurogenic, endocrinologic, drug-induced, or vasculogenic and in any male suffering from erectile dysfunction there may be more than one cause.
  • Female sexual dysfunction may also be categorized as psychogenic, neurogenic, endocrinologic, drug- induced, or vasculogenic and a female with one or more of these etiologies may also experience a lack of satisfaction in sexual relations.
  • Neurogenic impotence is often the result of anxiety or depression, with no apparent somatic or organic impairment.
  • Neurogenic impotence may arise from, for example, surgery or a pelvic injury, involving the nervous system affecting the penis or vagina.
  • Sexual dysfunction which is in endocrinologic in origin is most often associated with the disorders hypo- or hypergonadotropic hypogonadism and hyperprolactinein the male and decreases in estrogens in the female.
  • Vasculogenic sexual dysfunction is thought to be the most frequent cause of sexual dysfunction accounting for approximately fifty percent of all cases of organic sexual dysfunction.
  • the erectile dysfunction may be attributed to alterations in the flow of blood to and from the penis while in the female cases vaginal engorgement insufficiency and clitoral erectile insufficiency may be attributed to alterations in blood flow to the vagina and clitoris respectively.
  • Atherosclerotic or traumatic arterial occlusive disease to the arteries which supply blood to the penis can lead to a decrease in the rigidity of the erect penis as well as increase the time to achieving maximal erection.
  • Erectile insufficiency among male diabetics, particularly those with insulin-dependent diabetes mellitus.
  • Erectile dysfunction in male diabetics is often classified as "diabetogenic," although the underlying dysfunction is usually neurogenic and/or vasculogenic. About half of diabetic males suffer from erectile insufficiency, and about half of the cases of neurogenic impotence are in diabetics.
  • a significant population of female diabetics also exhibit symptoms of sexual dysfunction, especially those with complications directly attributed to the disease.
  • Sexual dysfunction in both males and females is sometimes a side effect of certain drugs, such as beta-antagonists that are administered to reduce blood pressure in persons suffering from hypertension, or drugs administered to treat depression or anxiety. Excessive alcohol consumption has also been linked to sexual dysfunction. These forms of sexual dysfunction may be regarded as iatrogenic sexual dysfunction.
  • a number of methods to treat sexual dysfunction are available. These treatments include pharmacological treatments, surgery and, in cases of psychogenic dysfunction, psychological counseling is sometimes effective. Psychogenic sexual dysfunction often can be cured by counseling. Insufficiency due to excessive alcohol consumption is sometimes cured by reducing or eliminating such consumption.
  • Papaverine is now widely used to treat impotence, although papaverine is ineffective in overcoming impotence due, at least in part, to severe atherosclerosis. Papaverine is effective in cases where the dysfunction is psychogenic or neurogenic and severe atherosclerosis is not involved.
  • anorectal diseases involve excessive anal sphincter tone.
  • anal fissures as well as acutely thrombosed external hemorrhoids are normally accompanied by severe anal pain.
  • Classical treatment of these conditions has usually involved surgery, however, in the treatment of more severe cases, surgical intervention is not without adverse side effects usually involving permanent sphincter defects and subsequent continence disturbances.
  • nitric oxide has been implicated as the chemical messenger mediating relaxation of the internal anal sphincter.
  • the local application of the exogenous nitric oxide (NO) donors nitroglycerin or isosorbide dinitrate has been reported to improve the symptoms and, in the case of anal fissure, facilitate the healing process.
  • Nitric oxide has been shown to mediate a number of actions including the bactericidal and tumoricidal actions of macrophages and blood vessel relaxation of endothelial cells. NO, and NO donors have also been implicated as mediators of nonvascular smooth muscle relaxation. This effect includes the dilation of the corpus cavernosum smooth muscle, an event involved in the penile and clitoral erection processes and the relaxation of the anal sphincter, an event necessary for normal defecation as well as an improvement in the symptoms of pain associated with many anal diseases. However, the effects of modified of phosphodiesterase inhibitors which are directly or indirectly linked with a nitric oxide adduct have not been investigated.
  • the invention provides novel nitrosated and nitrosylated phosphodiesterase inhibitors (NO n -PDE inhibitor) wherein n is 1 or 2.
  • the phosphodiesterase inhibitor can be nitrosylated or nitrosated through sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and nitrogen.
  • the invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
  • the invention provides a composition comprising a therapeutically effective amount of an phosphodiesterase inhibitor (PDE inhibitor), which can optionally be substituted with at least one NO or NO 2 moiety, and one to ten fold molar excess of a compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO + ) or nitroxyl (NO " ), or as the neutral species, nitric oxide (NO»).
  • PDE inhibitor phosphodiesterase inhibitor
  • the invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
  • the invention provides a method for treating male impotence in humans which comprises administering to an individual in need thereof a therapeutically effective amount of a nitrosated or nitrosylated PDE inhibitor .
  • the invention provides a method for treating male impotence in humans which comprises administering to an individual in need thereof a composition comprising a therapeutically effective amount of an PDE inhibitor which can optionally be substituted with at least one NO or N0 2 moiety, and a compound that donates, transfers or releases nitric oxide as a charged species, . e. , nitrosonium (NO + ) or nitroxyl (NO " ), or as the neutral species, nitric oxide (NO*).
  • the PDE inhibitor or PDE inhibitor directly or indirectly linked to at least one NO or NO 2 group, and nitric oxide donor can be administered separately or as components of the same composition.
  • the invention provides a method for treating female sexual dysfunction in humans which comprises administering to an individual in need thereof a therapeutically effective amount of a nitrosated or nitrosylated PDE inhibitor .
  • the invention provides a method for treating treating female sexual dysfunction in humans which comprises administering to an individual in need thereof a composition comprising a therapeutically effective amount of an PDE inhibitor which can optionally be substituted with at least one NO or NO 2 moiety, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO ) or nitroxyl (NO " ), or as the neutral species, nitric oxide (NO»).
  • the PDE inhibitor or PDE inhibitor directly or indirectly linked to at least one NO or NO 2 group, and nitric oxide donor can be administered separately or as components of the same composition.
  • the invention provides a method for treating anal disease resulting from excessive anal sphincter tone in humans which comprises administering to an individual in need thereof a therapeutically effective amount of a nitrosated or nitrosylated PDE inhibitor .
  • the invention provides a method for treating treating anal disease resulting from excessive anal sphincter tone in humans which comprises administering to an individual in need thereof a composition comprising a therapeutically effective amount of an PDE inhibitor which can optionally be substituted with at least one NO or NO 2 moiety, and a compound that donates, transfers or releases nitric oxide as a charged species, i. e. , nitrosonium (NO + ) or nitroxyl (NO " ), or as the neutral species, nitric oxide (NO » ).
  • the PDE inhibitor or PDE inhibitor directly or indirectly linked to at least one NO or NO 2 group, and nitric oxide donor can be administered separately or as components of the same composition.
  • nitrosated or nitrosylated PDE inhibitor and the compound that donates, transfers or releases nitric oxide and/or stimulates endogenous production of NO or EDRF in vivo can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • FIG. 1 Synthetic scheme for the preparation of nitrite containing substituted benzene derivatives.
  • FIG. 2 Synthetic scheme for the preparation of nitrosothiol containing substituted benzene derivatives.
  • FIG. 3 Synthetic scheme for the preparation of nitrate containing substituted benzene derivatives.
  • FIG. 4 Synthetic scheme for the preparation of nitrite containing imidazo[2,l-b]quinazoline derivatives.
  • FIG. 5 Synthetic scheme for the preparation of nitrosothiol containing imidazo[2,l-b]quinazoline derivatives.
  • Figure 7 Synthetic scheme for the preparation of nitrite containing purine-6-one derivatives.
  • Figure 8 Synthetic scheme for the preparation of nitrosothiol containing purine-6-one derivatives.
  • Figure 9 Synthetic scheme for the preparation of nitrate containing purine-6-one derivatives.
  • FIG. 10 Synthetic scheme for the preparation of nitrite containing pyrimidin-4-one derivatives.
  • FIG. 11 Synthetic scheme for the preparation of nitrosothiol containing pyrimidin-4-one derivatives.
  • Figure 12 Synthetic scheme for the preparation of nitrate containing pyrimidin-4-one derivatives.
  • FIG. 13 Synthetic scheme for the preparation of nitrite containing 2-pyridone derivatives.
  • FIG. 14 Synthetic scheme for the preparation of nitrosothiol containing 2-pyridone derivatives.
  • FIG. 15 Synthetic scheme for the preparation of nitrate containing 2-pyridone derivatives.
  • Figure 16 Synthetic scheme for the preparation of nitrite containing purine-2,6-dione derivatives.
  • FIG. 17 Synthetic scheme for the preparation of nitrosothiol containing purine-2,6-dione derivatives.
  • Figure 18 Synthetic scheme for the preparation of nitrate containing purine-2,6-dione derivatives.
  • Figure 19 Synthetic scheme for the preparation of nitrite containing quinoline derivatives.
  • Figure 20 Synthetic scheme for the preparation of nitrosothiol containing quinoline derivatives.
  • FIG. 21 Synthetic scheme for the preparation of nitrate containing quinoline derivatives.
  • FIG. 22 Synthetic scheme for the preparation of nitrite containing substituted pyridine derivatives.
  • FIG. 23 Synthetic scheme for the preparation of nitrosothiol containing substituted pyridine derivatives.
  • FIG. 24 Synthetic scheme for the preparation of nitrate containing substituted pyridine derivatives.
  • Figure 25 Synthetic scheme for the preparation of nitrite containing benzo[c] [l,6]naphthyridine derivatives.
  • Figure 27 Synthetic scheme for the preparation of nitrate containing benzo[c] [l,6]naphthyridine derivatives.
  • Figure 28 Synthetic scheme for the preparation of nitrite containing 2,6-dihydroxyalkylamino-4,8-dipiperidino pyrimido [5,4-d]pyrimidine derivatives.
  • Figure 30 Synthetic scheme for the preparation of nitrate containing 2,6-dihydroxyalkylamino-4,8-dipiperidino pyrimido [5,4-d]pyrimidine derivatives.
  • Figure 31 Synthetic scheme for the preparation of nitrite containing 1 -((3, 4-dihydroxyphenyl)methyl)-6,7-isoquinoline derivatives.
  • Figure 32 Synthetic scheme for the preparation of nitrosothiol containing 1 -((3 ,4-dihydroxyphenyl)methyl)-6,7-isoquinoline derivatives.
  • Figure 33 Synthetic scheme for the preparation of nitrate containing 1 -((3 ,4-dihydroxyphenyl)methyl)-6,7-isoquinoline derivatives.
  • Figure 34 Synthetic scheme for the preparation of nitrite containing substituted quinazoline derivatives.
  • Figure 36 Synthetic scheme for the preparation of nitrate containing substituted quinazoline derivatives.
  • FIG. 37 Synthetic scheme for the preparation of nitrite containing substituted phenol derivatives.
  • FIG. 38 Synthetic scheme for the preparation of nitrosothiol containing substituted phenol derivatives.
  • Figure 39 Synthetic scheme for the preparation of nitrate containing substituted phenol derivatives.
  • Figure 40 Graph of comparative in vitro relaxation effects of dipyridamole and Example 1 in phenylephrine induced contacted human corpus cavernosum tissue.
  • lower alkyl refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
  • alkoxy refers to R 50 O-wherein R 50 is lower alkyl as defined in this specification.
  • Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy and the like.
  • alkoxyalkyl refers to an alkoxy group as previously defined appended to an alkyl group as previously defined.
  • alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
  • hydroxy refers to -OH.
  • hydroxyalkyl refers to a hydroxy group as previously defined appended to a lower alkyl group as previously defined.
  • alkenyl refers to a branched or straight chain C 2 -C )0 hydrocarbon which also comprises one or more carbon-carbon double bonds.
  • amino refers to -NH 2 .
  • nitrate refers to -O-NO 2 .
  • alkylamino refers to R 50 NH-wherein R 50 is as defined in this specification, for example, methylamino, ethylamino, butylamino, and the like.
  • dialkylamino refers to R 52 R 53 N- wherein R 52 and R 5 are independently selected from lower alkyl groups as defined in this specification, for example dimethylamino, diethylamino, methyl propylamino and the like.
  • nitro refers to the group -NO 2 and “nitrosated” refers to compounds that have been substituted therewith.
  • nitroso refers to the group -NO and “nitrosylated” refers to compounds that have been substituted therewith.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, and nitro.
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • alkylaryl refers to a lower alkyl radical to which is appended an aryl group.
  • Representative arylalkyl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like.
  • arylalkoxy refers to an alkoxy radical to which is appended an aryl group.
  • Representative arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy and the like.
  • cycloalkyl refers to an alicyclic group comprising from 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • bridged cycloalkyl herein refers to two or more cycloalkyl radicals fused via adjacent or non-adjacent carbon atoms, including but not limited to adamantyl and decahydronapthyl.
  • cycloalkoxy refers to R 54 O- wherein R 54 is cycloalkyl as defined in this specification.
  • Representative examples of alkoxy groups include cyclopropoxy, cyclopentyloxy, and cyclohexyloxy and the like.
  • arylthio herein refers to R 55 S- wherein R 55 is an aryl group.
  • alkylsulfinyl herein refers to R 50 -S(O) 2 - wherein R 50 is as defined in this specification.
  • carbamoyl herein refers to -0-C(O)NH 2 .
  • carbonyl herein refers to -C(O)-.
  • halogen or halo as used herein refers to I, Br, Cl, or F.
  • haloalkyl refers to a lower alkyl radical to which is appended one or more halogens.
  • Representative examples of a haloalkyl group include trifluoromethyl, chloromethyl, 2-bromobutyl, 1 -bromo-2-chloro-pentyl and the like.
  • haloalkoxy refers to a haloalkyl radical to which is appended an alkoxy group.
  • Representative examples of haloalkoxy groups include, 1,1,1-trichloroethoxy, 2-bromobutoxy and the like.
  • heteroaryl refers to a mono- or bi- cyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring.
  • Heteroaryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro.
  • heteroaryl groups include but are not limited to pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, thiazole, isothiazole, benzothiazole, benzoxazole, thiadiazole, oxazole, pyrrole, imidazole and isoxazole.
  • heterocyclic ring refers to any 3-, 4-, 5-, 6-, or 7-membered nonaromatic ring containing at least one nitrogen atom, oxygen, or sulfur atom which is bonded to an atom which is not part of the heterocyclic ring.
  • arylheterocyclic ring refers to a bi- or tricyclic ring comprised of an aryl ring as previously defined appended via two adjacent carbons of the aryl group to a heterocyclic ring as previously defined.
  • heterocyclic compounds herein refers to mono and polycyclic compounds containing at least one heteroaryl or heterocyclic ring.
  • amido refers to -NH-C(O)-R 56 wherein R 56 is a lower akyl, aryl, or hereroaryl group as defined in this specification
  • alkylamido refers to R 50 N-C(O)-R 56 wherein R 50 is as defined in this specification and R 56 is a lower akyl, aryl, or hereroaryl goup as defined in this specification.
  • contemplated PDE inhibitors to which a nitric oxide adduct may be directly or indirectly linked include dipyridamole, zaprinast, sildenafil, filaminast, denbufyllene, piclamilast, zardaverine, rolipram, papaveroline, E4021, and triflusal.
  • a principal aspect of the invention relates to novel nitrosated and/or nitrosylated phosphodiesterase inhibitors.
  • Ri is alkoxy, cycloalkoxy, halogen, or
  • R 2 is hydrogen, alkoxy, or haloalkoxy; and R 3 is selected from:
  • D is selected from (i) -NO; (ii) -N0 2 ; (iii) -C(R d )-O-C(O)-Y-Z-[C(R e )(R f )] p -T-Q in which R d is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl, aryl or heteroaryl, Y is oxygen, sulfur, or NRj in which Rj is hydrogen, lower alkyl, Rg and R f at each occwrence are independently selected from hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, amino, alkylamino, amido, alkylamido, dialkylamino, carboxy, or taken together are carbonyl, cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6, T is a covalent bond, oxygen, sulfur or nitrogen, Z is selected from
  • R 4 is selected from (i) hydrogen, (ii) -C(R d )-O-C(O)-Y-Z-[C(R e )(R f )] p -T-Q, (iii) -C(O)-T 1 -[C(R e )(R f )] p - T 2 -Q, (iv) -C(O)-Z-[G-[C(R )(R f )] p -T-Q] p ; and wherein R R., R f , p, G, T, T , T , Q, Y, and Z are defined as in this specification;
  • R 5 is selected from a lone pair of electrons or -C(R d )-O-C(O)-Y-Z-[C(R e )(R f )] p -T- Q wherein Rj, R e , R f , p, T, T , T , Q, Y, and Z are defined as in this specification;
  • R] [ and R l2 are independently selected from hydrogen or Ri wherein R is as defined in this specification with the provision that Ri 1 and R t2 are not both hydrogen;
  • X is a halogen and
  • Di is selected from D or hydrogen and wherein D is as defined in this specification.
  • R is as defined in this specification; R 8 is selected from hydrogen or lower alkyl; R 9 is selected from hydrogen or halogen; and Rio is selected from: (i) hydrogen
  • R 8 is as defined in this specification.
  • E is selected from nitrogen or -CH-; G is selected from nitrogen or -C(R 8 )-; R 2 ⁇ is selected from:
  • R 22 is selected from R 1 or lower alkyl
  • R 8 , R ⁇ , and R 12 are as defined in this specification.
  • F is selected from -CH 2 - or sulfur
  • R and R 8 are as defined in this specification.
  • R ⁇ 3 is selected from:
  • Rg and R 7 are independently selected from hydrogen or j wherein R 4 is as defined in this specification.
  • R is as defined in this specification; and R ⁇ 4 is selected from: (i) ( ⁇ )
  • R ⁇ is as defined in this specification.
  • R 15 is hydrogen, lower alkyl, R,, or -(CH 2 ) 4 -C(CH 3 ) 2 -0-D ⁇ ;
  • Ri 6 is lower alkyl
  • R is hydrogen, lower alkyl, CH 3 -C(O)-CH 2 -, CH 3 -O-CH 2 -, or D with the provision that either R [5 or R[ 7 must be selected to contain D and wherein D and D ⁇ are as defined in this specification.
  • R i8 is selected from:
  • R 19 is selected from:
  • R 4 , Rn, and R ⁇ 2 are defined as in this specification.
  • R 20 is selected from:
  • a is an integer from 2 to 3 and D and Di are defined as in this specification.
  • D and D t are defined as in this specification.
  • J is selected from:
  • K is selected from:
  • V is carbon or nitrogen
  • R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , and R 30 are independently selected from hydrogen, halogen, alkoxy, nitrile, carboxamido, or carboxy 1; and wherein p, R e , R f , T, T 1 , T 2 , Y and D are defined as in this specification.
  • R 3 ⁇ is alkyl, halogen, haloalkyl, or haloalkoxy; R 32 is selected from Di or -C(O)-R 8 ; and wherein Di and R 8 are defined as in this specification.
  • Compounds of the invention which have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. It is to be understood that the present invention anticipates and includes within its scope all such isomers and mixtures thereof.
  • Another aspect of the invention provides processes for making the novel compounds of the invention and to the intermediates useful in such processes.
  • Rl 3 Rl 4 , Rl5> R-16> Rl7> Rl8> Rl > R-20, R2I 5 R22> , R 23 > R 24 .
  • R 31 , R 32 , R ⁇ , R f , a, p, D, D ] ; E, F, G, J, K, and X are as defined in this specification or as depicted in the reaction schemes for structures I-XIII; P is an oxygen protecting group and P is a sulfur protecting group.
  • the reactions are performed in solvents appropriate to the reagents and materials employed are suitable for the transformations being effected. It is understood by those skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions.
  • Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to skilled practitioners in the art.
  • sulfur and oxygen protecting groups is well known in the art for protecting thiol and alcohol groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, c.f., T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1991).
  • Nitroso compounds of formula (I) wherein R b R 2 , Rg, R f , and p are defined as in this specification and a nitrite containing imide is representative of the R 3 group as defined in this specification may be prepared as outlined in Figure 1.
  • the amide group of formula 1 is converted to the imide of formula 2 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P is as defined in this specification.
  • Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl ether, a tert- butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether.
  • Deprotection of the hydroxyl moiety is the preferred method for removing silyl ether protecting groups
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IA.
  • Nitroso compounds of formula (I) wherein R ls R 2 , Rg, R f , and p are defined as in this specification and a nitrosothiol containing imide is representative of the R group as defined in this specification may be prepared as outlined in Figure 2.
  • the amide group of formula 1 is converted to the imide of formula 3 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined in this specification.
  • Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide and protected thiol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thiocarbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such
  • Nitro compounds of formula (I) wherein R R 2 , R e , R f , and p are defined as in this specification and an nitrate containing imide is representative of the R 3 group as defined in this specification may be prepared as outlined in Figure 3.
  • the amide group of the formula 1 is converted to the imide of the formula 4 wherein p, R e and R f are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent.
  • Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Preferred halides are bromide and iodide. Reaction of the imide of the formula 4 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula lC.
  • Another embodiment of this aspect provides processes for making compounds having structures II and to the intermediates useful in such processes as follows.
  • Nitroso compounds of formula (II) wherein R 8 , R 9 , Rio, R-, R f , and p are defined as in this specification, and a nitrite containing amide is representative of the t group as defined in this specification may be prepared as outlined in Figure 4.
  • the imidazo[2,l- b]quinazoline of formula 5 is converted to the acy limidazo [2, 1-b] quinazoline of formula 6 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P 1 is as defined in this specification.
  • acylimidazo[2,l- bjquinazolines are reacting the imidazo[2,l-b]quinazoline with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the imidazo[2,l-b]quinazoline and protected alcohol containing acid in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or l-ethyl-3 (3 -dimethylaminopropyl) carbodiimide hydrochloride (ED AC HC1) with or without a catalyst such as 4-dimethylaminopyridine (DMAP) or 1 -hydroxybenzotriazole (HOBt).
  • a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or l-ethyl-3 (3 -dimethylaminopropyl) carbodiimide hydrochloride (ED AC HC1)
  • DCC dicyclohexy
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or tert-butyldimethylsilyl ether.
  • Deprotection of the hydroxyl moiety fluoride ion is the prefe ⁇ ed method for removing silyl ether protecting groups
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula HA.
  • Nitroso compounds of formula (II) wherein R 8 , R 9 , Rj 0 , R e , R f , and p are defined as in this specification, and a nitrosothiol containing amide is representative of the R 4 group as defined in this specification may be prepared as outlined in Figure 5.
  • the imidazo [2, 1-b] quinazoline of formula 5 is converted to the acylimidazo[2,l- bjquinazoline of formula 7 wherein p, R. and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of acylated imidazo[2,l-b]quinazolines are reacting the imidazo[2,l-b]quinazoline with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the imidazo[2,l-b]quinazoline and protected thiol containing acid in the presence of a dehydrating agent such as DCC or EDAC HC1 with or without a catalyst such as DMAP or HOBt.
  • a dehydrating agent such as DCC or EDAC HC1
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thiocarbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable
  • Nitro compounds of formula (II) wherein R 8 , R 9 , R] 0 , R e , R f , and p are defined as in this specification, and a nitrate containing amide is representative of the j group as defined in this specification may be prepared as outlined in Figure 6.
  • the imidazo[2,l- bjquinazoline of formula 5 is converted to the acylimidazo[2,l-b]quinazoline of formula 8 wherein p, Rg and R f are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent.
  • Prefe ⁇ ed methods for the formation of the acylimidazo[2,l-b]quinazolines are reacting the imidazo[2,l- bjquinazoline with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the alcohol and halide containing acid in the presence of a dehydrating agent such as DCC or ED AC HC1 with or without a catalyst such as DMAP or HOBt.
  • Prefe ⁇ ed halides are bromide and iodide.
  • Another embodiment of this aspect provides processes for making compounds having structures III and to the intermediates useful in such processes as follows.
  • Nitroso compounds of formula (III) wherein E, G, R 2b R 22 , Rg, R f , and p are defined as in this specification and a nitrite containing amide is representative of the R group as defined in this specification may be prepared as outlined in Figure 7.
  • the purine-6-one group of formula 9 is converted to the acylated purine-6-one of formula 10 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of acylated purine-6-ones are reacting the purine-6-one with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether.
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IIIA.
  • Nitroso compounds of formula (III) wherein E, G, R 2 ⁇ , R 22 , R e , R f , and p are defined as in this specification and an nitrosothiol containing amide is representative of the R group as defined in this specification may be prepared as outlined in Figure 8.
  • the purine-6-one group of formula 9 is converted to the acylated purine-6-one of formula 11 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P 2 is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of acylated purine-6-ones are reacting the purine-6-one with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid.
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable
  • Nitro compounds of formula (III) wherein E, G, R 2 ⁇ , R 22 , R e , R f , and p are defined as in this specification and an nitrate containing amide is representative of the Rn group as defined in this specification may be prepared as outlined in Figure 9.
  • the purine-6- one of formula 9 is converted " to the acylated purine-6-one the of formula 12 wherein p, R e and R f are defined and X is halogen.
  • Prefe ⁇ ed methods for the formation of acylated purine-6-ones are reacting the purine-6-one with the preformed acid chloride or symmetrical anhydride of the halide containing acid.
  • Prefe ⁇ ed halides are bromide and iodide.
  • Reaction of the of the acylated purine-6-one of the formula 12 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula IIIC.
  • Another embodiment of this aspect provides processes for making compounds having structures IV and to the intermediates useful in such processes as follows.
  • Nitroso compounds of formula (IV) wherein F, R 8: R 13 , R e , R f , and p are defined as in this specification and a nitrite containing acyl hydrazide is representative of the group as defined in this specification may be prepared as outlined in Figure 10.
  • the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine of formula 13 is converted to the 3 (2- acyl)-pyridazinone or 2-acyl-l, 2, 3, 4-thiadiazine of formula 14 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of 3 (2-acyl)-pyridazinone or 2-acyl-l, 2, 3, 4- thiadiazine are reacting the 3 (2H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine and protected alcohol containing acid in the presence of a dehydrating agent such as DCC or EDAC .
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether.
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IV A.
  • Nitroso compounds of formula (IV) wherein F, R 8] R ⁇ 3 , g, R f , and p are defined as in this specification and a nitrosothiol containing acyl hydrazide is representative of the ⁇ group as defined in this specification may be prepared as outlined in Figure 11.
  • the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine of formula 13 is converted to the 3 (2- acyl)-pyridazinone or 2-acyl-l, 2, 3, 4-thiadiazine of formula 15 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of 3 (2-acyl)-pyridazinones or 2-acyl-l, 2, 3, 4-thiadiazines are reacting the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine and protected thiol containing acid in the presence of a dehydrating agent such as DCC or EDAC .
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6- trimethoxybenzyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine
  • the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine of formula 13 is converted to the 3 (2- acyl)-pyridazinone or 2-acyl-l, 2, 3, 4-thiadiazine of formula 16 wherein p, R g and R are defined and X is halogen.
  • Prefe ⁇ ed methods for the formation of 3 (2-acyl)- pyridazinones or 2-acyl-l, 2, 3, 4-thiadiazines are reacting the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4- thiadiazine and halide containing acid in the presence of a dehydrating agent such as DCC or EDAC .
  • Prefe ⁇ ed halides are bromide and iodide.
  • Another embodiment of this aspect provides processes for making compounds having structures V and to the intermediates useful in such processes as follows.
  • Nitroso compounds of formula (V) wherein R 14 , R e , R f , and p are defined as in this specification and an nitrite containing imide is representative of the R 4 group as defined in this specification may be prepared as outlined in Figure 13.
  • the amide group of formula 17 is converted to the imide of formula 18 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert- butyldiphenylsilyl ether.
  • Nitroso compounds of formula (V) wherein R ⁇ 4 , R e , R f , and p are defined as in this specification and a nitrosothiol containing imide is representative of the R 4 group as defined in this specification may be prepared as outlined in Figure 14.
  • the amide group of formula 17 is converted to e imide of formula 19 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide and protected thiol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thiocarbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable
  • Nitro compounds of formula (V) wherein R 14 , R e , R f , and p are defined as in this specification and a nitrate containing imide is representative of the R t group as defined in this specification may be prepared as outlined in Figure 15.
  • the amide group of the formula 17 is converted to the imide of the formula 20 wherein p, R ⁇ , and R f are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent.
  • Prefe ⁇ ed methods for the formation of imides are reacting the amide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed halides are bromide and iodide.
  • Reaction of the imide of the formula 20 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula VC.
  • Another embodiment of this aspect provides processes for making compounds having structures VI and to the intermediates useful in such processes as follows.
  • the 1H- purine-2, 6-dione of formula 21 is converted to the acylated derivative of the formula 22 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of acylated lH-purine-2, 6-diones are reacting the lH-purine-2, 6-dione with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the lH-purine-2, 6- dione and protected alcohol containing acid in the presence of a dehydrating agent such as DCC or EDAC .
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldimethylsilyl ether.
  • Nitroso compounds of formula (VI) wherein R i 5 , R 16 , Rg, R f , and p are defined as in this specification and a nitrosothiol containing acyl imidazolide is representative of the R ⁇ group as defined in this specification may be prepared as outlined in Figure 17.
  • the lH-purine-2, 6-dione of formula 21 is converted to the acylated derivative of the formula 23 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of acylated lH-purine-2, 6- diones are reacting the lH-purine-2, 6-dione with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the 1H- purine-2, 6-dione and protected thiol containing acid in the presence of a dehydrating agent such as DCC or EDAC .
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thiocarbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable
  • Nitro compounds of formula (VI) wherein R ⁇ 5 , R ⁇ 6 , R e , R f , and p are defined as in this specification and an O-nitrosated acylated lH-purine-2, 6-dione is representative of the R 17 group as defined in this specification may be prepared as outlined in Figure 18.
  • the lH-purine-2, 6-dione of the formula 21 is converted to the acylated derivative of the formula 24 wherein p, R e and R f are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent.
  • Prefe ⁇ ed methods for the formation of acylated lH-purine-2, 6-diones are reacting the lH-purine- 2, 6-dione with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the lH-purine-2, 6-dione and halide containing acid in the presence of a dehydrating agent such as DCC or ED AC .
  • Prefe ⁇ ed halides are bromide and iodide.
  • Another embodiment of this aspect provides processes for making compounds having structures VII and to the intermediates useful in such processes as follows.
  • Nitroso compounds of formula (VII) wherein R 8 , R[ 8 , R e , R , and p are defined as in this specification and a nitrite containing imide is representative of the R t group as defined in this specification may be prepared as outlined in Figure 19.
  • the amide nitrogen of formula 25 is converted to the imide of formula 26 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert- butyldiphenylsilyl ether.
  • Nitroso compounds of formula (VII) wherein R 8 , R ⁇ 8 , R e , R f , and p are defined as in this specification and a nitrosothiol containing imide is representative of the R 4 group as defined in this specification may be prepared as outlined in Figure 20.
  • the amide nitrogen of formula 25 is converted to the imide of formula 27 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide and protected thiol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thiocarbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable
  • Nitro compounds of formula (VII) wherein R 8 , R ⁇ 8 , Rg, R f , and p are defined as in this specification and a nitrate containing imide is representative of the t group as defined in this specification may be prepared as outlined in Figure 21.
  • the amide group of the formula 25 is converted to the imide of the formula 28 wherein p, Rg and R f are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent.
  • Prefe ⁇ ed methods for the formation of imides are reacting the amide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed halides are bromide and iodide.
  • Reaction of the imide of the formula 28 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula VIIC.
  • Another embodiment of this aspect provides processes for making compounds having structures VIII and to the intermediates useful in such processes as follows.
  • Nitroso compounds of formula (VIII) wherein Rg, R f , and p are defined as in this specification and a nitrite containing imide is representative of the R] 9 group as defined in this specification may be prepared as outlined in Figure 22.
  • the amide nitrogen of formula 29 is converted to the imide of formula 30 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert- butyldiphenylsilyl ether.
  • Nitroso compounds of formula (VIII) wherein Rg, R f , and p are defined as in this specification and a nitrosothiol containing imide is representative of the R[ 9 group as defined in this specification may be prepared as outlined in Figure 23.
  • the amide nitrogen of formula 29 is converted to the imide of formula 31 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thiocarbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable
  • Nitro compounds of formula (VIII) wherein Rg, R f , and p are defined as in this specification and a nitrate containing imide is representative of the R ⁇ 9 group as defined in this specification may be prepared as outlined in Figure 24.
  • the amide group of the formula 29 is converted to the imide of the formula 32 wherein p, Rg and R f are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent.
  • Prefe ⁇ ed methods for the formation of imides are reacting the amide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed halides are bromide and iodide.
  • Reaction of the imide of the formula 32 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula VIIIC.
  • Nitroso compounds of formula (IX) wherein R 20 , Rg, R f , and p are defined as in this specification and an nitrate containing imide or sulfonimide is representative of the R group as defined in this specification may be prepared as outlined in Figure 25.
  • the amide or sulfonamide nitrogen of formula 33 is converted to the imide or sulfonimide of formula 34 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P 1 is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of imides or sulfonimides are reacting the amide or sulfonimide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide or sulfonimide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert- butyldiphenylsilyl ether.
  • Nitroso compounds of formula (IX) wherein R 20 , Rg, R f , and p are defined as in this specification and an nitrosothiol containing imide or sulfonimide is representative of the t group as defined in this specification may be prepared as outlined in Figure 26.
  • the amide or sulfonamide nitrogen of formula 33 is converted to the imide or sulfonimide of formula 35 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P 2 is as defined in this specification..
  • Prefe ⁇ ed methods for the formation of imides or sulfonimides are reacting the amide or sulfonimide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide or sulfonimide and protected thiol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thiocarbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable
  • Nitro compounds of formula (IX) wherein R 20 , R e , R f , and p are defined as in this specification and a nitrate containing imide or sulfonimide is representative of the R 4 group as defined in this specification may be prepared as outlined in Figure 27.
  • the amide or sulfonamide group of the formula 33 is converted to the imide or sulfonimide of the formula 36 wherein p, Rg and R f are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent.
  • Prefe ⁇ ed methods for the formation of imides or sulfonimides are reacting the amide or sulfonamide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide or sulfonamide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
  • Prefe ⁇ ed halides are bromide and iodide.
  • Reaction of the imide or sulfonimide of the formula 36 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula IXC.
  • Another embodiment of this aspect provides processes for making compounds having structures X and to the intermediates useful in such processes as follows.
  • Nitroso compounds of formula (X) wherein Di, Rg, R f , , and p are defined as in this specification and a nitrite containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 28.
  • the alcohol group of formula 37 is converted to the ester of formula 38 wherein p, R « and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the alcohol and protected alcohol containing acid with a dehydrating agent such as DCC or ED AC.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert- butyldimethylsilyl ether.
  • Nitroso compounds of formula (X) wherein Di, Rg, R f , and p are defined as in this specification and a nitrosothiol containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 29.
  • the alcohol group of the formula 37 is converted to the ester of the formula 39 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the alcohol and protected thiol containing acid with a dehydrating agent such as DCC or EDAC. HC1 in the presence of a catalyst such as DMAP or HOBt..
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thiocarbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction a suitable nitrosylating agent such ' as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous
  • Nitro compounds of formula (X) wherein D b R ⁇ , R f , and p are defined as in this specification and a nitrate containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 30.
  • the alcohol group of the formula 37 is converted to the ester of the formula 40 wherein p, Rg and R f are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent.
  • Prefe ⁇ ed methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the alcohol and halide containing acid with a dehydrating agent such as DCC or ED AC.
  • HC1 in the presence of a catalyst such as DMAP or HOBt.
  • a catalyst such as DMAP or HOBt.
  • Prefe ⁇ ed halides are bromide and iodide.
  • Reaction of the ester of the formula 40 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula XC.
  • Nitroso compounds of formula (XI) wherein Di, Rg, R f , and p are defined as in this specification and a nitrite containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 31.
  • the alcohol group of formula 41 is converted to the ester of formula 42 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the alcohol and protected alcohol containing acid with a dehydrating agent such as DCC or ED AC.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert- butyldimethylsilyl ether.
  • Nitroso compounds of formula (XI) wherein Di, Rg, R f , and p are defined as in this specification and a nitrosothiol containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 32.
  • the alcohol group of the formula 41 is converted to the ester of the formula 43 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the alcohol and protected thiol containing acid with a dehydrating agent such as DCC or ED AC. HC1 in the presence of a catalyst such as DMAP or HOBt..
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a disulfide, a thioester such as a thioacetate or thiobenzoate, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S- triphenylmethyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent
  • esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the alcohol and halide containing acid with a dehydrating agent such as DCC or EDAC. HC1 in the presence of a catalyst such as DMAP or HOBt. Preferred halides are bromide and iodide. Reaction of the ester of the formula 44 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula XIC.
  • a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula XIC.
  • Another embodiment of this aspect provides processes for making compounds having structures XII and to the intermediates useful in such processes as follows.
  • Nitroso compounds of formula (XII) wherein Rg, R f , R 3 , R 24 , R 25 , J, V and p are defined as in this specification and a nitrite containing thioester is representative of theK-T-D group as defined in this specification may be prepared according to Scheme 34.
  • the carboxylic acid group of formula 45 is converted to the thioester of formula 46 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected alcohol containing thiol agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of thioesters are reacting the thiol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC. HC1 in the presence of a catalyst such as DMAP or HOBt.
  • a dehydrating agent such as DCC or EDAC.
  • HC1 in the presence of a catalyst such as DMAP or HOBt.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • Nitroso compounds of formula (XII) wherein Rg, R f , R 23 , R 24 , R 25 , J, V and p are defined as in this specification and a nitrosothiol containing thioester is representative of the K-T-D group as defined in this specification may be prepared according to Scheme 35.
  • the carboxylic acid group of formula 45 is converted to the thioester of formula 47 wherein p, R e and R f are defined as in this specification by reaction with an appropriate mono protected dithiol.
  • Prefe ⁇ ed methods for the formation of thioesters are reacting the free thiol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the free thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC. HC1 in the presence of a catalyst such as DMAP or HOBt.
  • a dehydrating agent such as DCC or EDAC.
  • HC1 in the presence of a catalyst such as DMAP or HOBt.
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a disulfide, a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.
  • Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group).
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate
  • a suitable anhydrous solvent such as methyene chloride, THF, DMF, or acetonitrile with or without an amine base such
  • Nitro compounds of formula (XII) wherein Rg, R f , R 23 , R 24 , R 25 , J, V and p are defined as in this specification and a nitrate containing thioester is representative of the K-T-D group as defined in this specification may be prepared according to Scheme 36.
  • the carboxylic acid group of formula 45 is converted to the thioester of formula 46 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected alcohol containing thiol agent wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of thioesters are reacting the thiol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC. HC1 in the presence of a catalyst such as DMAP or HOBt.
  • a dehydrating agent such as DCC or EDAC.
  • HC1 in the presence of a catalyst such as DMAP or HOBt.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • Nitroso compounds of formula (XIII) wherein Rg, R f , R 3 ⁇ , R 32 , and p are defined as in this specification and a nitrite containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 37.
  • the carboxylic acid group of formula 48 is converted to the ester of formula 49 wherein p, Rg and R f are defined as in this specification by reaction with an monoprotected protected diol wherein P 1 is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the alcohol and carboxylic acid with a dehydrating agent such as DCC or EDAC.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • Nitroso compounds of formula (XIII) wherein g, R f , R 3 ⁇ , R 32 , and p are defined as in this specification and a nitrosothiol containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 38.
  • the carboxylic acid group of formula 48 is converted to the ester of formula 50 wherein p, R e and R f are defined as in this specification by reaction with an appropriate protected thiol containing alcohol.
  • Prefe ⁇ ed methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the primary thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC.
  • Prefe ⁇ ed protecting groups for the thiol moiety are as a disulfide, a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.
  • Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are prefe ⁇ ed methods for reducing disulfide groups while mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group).
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate
  • a suitable anhydrous solvent such as methyene chloride, THF, DMF, or acetonitrile with or without an amine base such as
  • Nitro compounds of formula (XIII) wherein Rg, R , R 3 i , R 32 , and p are defined as in this specification and a nitrate containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 39.
  • the carboxylic acid group of formula 48 is converted to the ester of formula 49 wherein p, Rg and R f are defined as in this specification by reaction with an appropriate monoprotected protected diol wherein P is as defined in this specification.
  • Prefe ⁇ ed methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the alcohol and carboxylic acid with a dehydrating agent such as DCC or EDAC.
  • Prefe ⁇ ed protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the prefe ⁇ ed method for removing silyl ether protecting groups) followed by reaction of the alcohol with a suitable nitrating agent such as nitric acid and acetic anhydride in ethyl acetate/acetic acid affords the compound of the formula XIIIC.
  • carboxylic acid group of the formula 48 is converted to the ester of the formula 51 wherein p, Rg and R f are defined as in this specification and X is a halogen by reaction with an appropriate halide containing alcohol.
  • Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the alcohol and halide containing alcohol with a dehydrating agent such as DCC or EDAC. HC1 in the presence of a catalyst such as DMAP or HOBt.
  • Preferred halides are bromide and iodide.
  • Reaction of the ester of the formula 51 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula XIIIC.
  • compositions comprising (i) a therapeutically effective amount of a PDE inhibitor, which optionally can be substituted with at least one NO or NO 2 group or a group that stimulates endogenous production of NO or EDRF in vivo, and (ii) a compound that donates, transfers or releases nitrogen monoxide as a charged species, i. e. , nitrosonium (NO + ) or nitroxyl (NO " ), or as the neutral species, nitric oxide (NO-) and/or a compound that stimulates endogenous production of NO or EDRF in vivo.
  • a PDE inhibitor which optionally can be substituted with at least one NO or NO 2 group or a group that stimulates endogenous production of NO or EDRF in vivo
  • a compound that donates, transfers or releases nitrogen monoxide as a charged species i. e. , nitrosonium (NO + ) or nitroxyl (NO " ), or as the neutral species, nitric oxide
  • the compounds that donate, transfer or release nitric oxide can be any of those known to the art, including those mentioned and/or exemplified below.
  • Nitrogen monoxide can exist in three forms: NO " (nitroxyl), NO- (nitric oxide) and NO + (nitrosonium).
  • NO- is a highly reactive short-lived species that is potentially toxic to cells. This is critical, because the pharmacological efficacy of NO depends upon the form in which it is delivered.
  • NO- nitrosonium and nitroxyl do not react with O or O 2 " species. Consequently, administration of NO equivalents does not result in the generation of toxic by-products or the elimination of the active NO moiety.
  • nitric oxide and compounds that release nitric oxide or otherwise directly or indirectly deliver or transfer nitric oxide to a site of its activity, such as on a cell membrane, in vivo.
  • nitric oxide encompasses uncharged nitric oxide (NO-) and charged nitric oxide species, particularly including nitrosonium ion (NO ) and nitroxyl ion (NO " ).
  • NO- uncharged nitric oxide
  • NO nitrosonium ion
  • NO nitroxyl ion
  • the reactive form of nitric oxide can be provided by gaseous nitric oxide.
  • nitric oxide releasing, delivering or transfe ⁇ ing compounds having the structure F-NO wherein F is a nitric oxide releasing, delivering or transfe ⁇ ing moiety, include any and all such compounds which provide nitric oxide to its intended site of action in a form active for their intended purpose.
  • NO adducts encompasses any of such nitric oxide releasing, delivering or transferring compounds, including, for example, S- nitrosothiols, S-nitrothiols, O-nitrosoalcohols, O-nitroalcohols, sydnonimines, 2- hydroxy-2-nitrosohydrazines (NONOates), (E)-alkyl-2-[(E)-hydroxyimino]-5-nitro-3- hexene amines or amides, nitrosoamines, as well a subtstates for the endogenous enzymes which synthesize nitric oxide.
  • any or all of these "NO adducts" can be mono- or poly-nitrosylated or nitrosated at a variety of naturally susceptible or artificially provided binding sites for nitric oxide or derivatives which donate or release NO.
  • S-nitrosothiols are compounds that include at least one -S-NO group.
  • Such compounds include S-nitroso-polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars, S-nitrosylated-modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides); and an S-nitrosylated hydrocarbons where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; S-nitrosylated hydrocarbons having one or more substituent groups in addition to the S-nitroso group; and heterocyclic compounds.
  • One particularly prefe ⁇ ed embodiment of this aspect relates to S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof.
  • such compounds include the following: S- nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-- cysteine and S-nitroso-glutathione.
  • Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur group on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins, such as lipoproteins, heme proteins such as hemoglobin and serum albumin; and biologically protective proteins, such as the immunoglobulins and the cytokines.
  • TPA tissue-type plasminogen activator
  • cathepsin B transport proteins, such as lipoproteins, heme proteins such as hemoglobin and serum albumin
  • biologically protective proteins such as the immunoglobulins and the cytokines.
  • nitrosylated proteins are described in PCT Publ. Applic. No. WO 93/09806, published May 27, 1993. Examples include polynitrosylated albumin where multiple thiol or other nucleophilic centers in the protein are modified.
  • S-nitrosothiols include those having the structures:
  • x equals 2 to 20; R ⁇ and R f are as defined in this specification; and B is selected from the group consisting of fluoro, C ⁇ -C 6 alkoxy, cyano, carboxamido, cycloalkyl, arylalkoxy, alkylsulfinyl, arylthio, alkylamino, dialkylamino, hydroxy, carbamoyl, N- alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl.
  • Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaNO 2 under acidic conditions (pH is about 2.5) to yield the S-nitroso derivative. Acids which may be used for this purpose include aqueous sulfuric, acetic and hydrochloric acids. Alternatively, the precursor thiol may be nitrosylated by treatment with an alkyl nitrite such as tert-butyl nitrite.
  • NO adducts are those wherein the compounds donate, transfer or release nitric oxide and are selected from the group consisting of compounds that include at least one ON-N- or ON-C- group.
  • the compound that includes at least one ON-N- or ON-C- group is preferably selected from the group consisting of ON-N- or ON-C-polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); ON-N- or ON-C-amino acids(including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ON-N- or ON-C-sugars; ON-N- or ON-C- modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides), ON-O-, ON-N- or ON-C-hydrocarbons which can be branched or unbranched, saturated or unsaturated aliphatic hydrocarbons or
  • NO adducts Another group of such NO adducts is the nitrites which have an -O-NO group wherein the organic template to which the nitrite group is appended is a protein, polypeptide, amino acid, carbohydrate, branched or unbranched and saturated or unsaturated alkyl, aryl or a heterocyclic compound.
  • a prefe ⁇ ed example is the nitrosylated form of isosorbide.
  • Compounds in this group form S-nitrosothiol intermediates in vivo in the recipient human or other animal to be treated and can therefore include any structurally analogous precursor R-O-NO of the S-nitrosothiols described above.
  • nitrates which donate, transfer or release nitric oxide and are selected from the group consisting of compounds that include at least one at least one O 2 N-O-, O N-N-, O 2 N-S- or O 2 N-C- group.
  • O 2 N-O-, O N-N-, O 2 N-S- or O 2 N-C-polypeptides are those selected from the group consisting of O 2 N-O-, O 2 N-N-, O 2 N-S- or O 2 N-C-polypeptides; O 2 N-O-, O 2 N-N-, O 2 N-S- or O 2 N-C-amino acids; O 2 N-O-, O 2 N-N- O 2 N-S- or O 2 N-C- sugars; O 2 N-O-, O 2 N-N-, O 2 N-S- or O 2 N-C-modified and unmodified oligonucleotides; O 2 N-O-, O 2 N-N-, 0 2 N-S- or O 2 N-C- hydrocarbons which can be branched or unbranched, saturated or unsaturated aliphatic hydrocarbons or aromatic hydrocarbons; O 2 N-O-, O 2 N-N-, O 2 N-
  • R includes polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); sugars; modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides); and a hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; hydrocarbons having one or more substituent groups in addition to the A- nitroso group; and heterocyclic compounds.
  • polypeptide includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); sugars; modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleot
  • A is S, O, or N
  • u and v are each integers independently selected from 1, 2 and 3
  • M is a metal, preferably a transition metal.
  • Prefe ⁇ ed metals include iron, copper, manganese, cobalt, selenium and luthidium. Also contemplated are N-nitrosylated metal centers such as nitroprusside.
  • 2-hydroxy-2-nitrosohydrazines which donate, transfer or release nitric oxide and have a and R ⁇ 2 include polypeptides, amino acids, sugars, modified and unmodified oligonucleotides, hydrocarbons where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon or an aromatic hydrocarbon, hydrocarbons having one or more substituent groups and heterocyclic compounds.
  • M is a metal cation, such as, for example, a Group I metal cation.
  • thionitrates which donate, transfer or release nitric oxide and have the structure Rg ⁇ -S-NO 2 wherein R ⁇ is as described above.
  • Compounds that stimulate endogenous synthesis of NO or EDRF in vivo include L-arginine, the substrate for nitric oxide synthase, cytokines, adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein, and endothelin.
  • the nitric oxide When administered in vivo, the nitric oxide may be administered in combination with pharmaceutical carriers and in dosages described herein.
  • the nitrosated or nitrosylated compounds of the invention are used at dose ranges and over a course of dose regimen and are administered in the same or substantially equivalent vehicles/carrier by the same or substantially equivalent oral or nasal inhalant devices as their non-nitrosated or non-nitrosylated counterparts.
  • the nitrosated or nitrosylated compounds of the invention can also be used in lower doses and in less extensive regimens of treatment.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination.
  • the dosage regimen actually employed may vary widely and therefore may deviate from the prefe ⁇ ed dosage regimen set forth above.
  • Total daily dose administered to a host in single or divided doses may be in amounts, for example, from about 1 to about 100 mg/kg body weight daily and more usually about 3 to 30 mg/kg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • compositions of the invention can also be administered as described above or can be made to include one or more additional active compounds which are known to be effective against the specific disease state is targeted for treatment.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • Example 2b The product of Example 2b (0.314 g, 1.4 mmol) was dissolved in methanol (10 ml) and solid sodium hydroxide (85 mg, 2.1 mmol) was added. After stirring 5 minutes, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate, followed by brine, and then dried over anhydrous sodium sulfate. The volatile components were evaporated in vacuo leaving the title compound as a colorless oil (0.188 g, 75 % yield) which was used without further purification.
  • Human corpus cavernosum tissue biopsies were obtained at the time of penile prosthesis implantation from impotent men.
  • the tissue was maintained in a chilled Krebs-bicarbonate solution prior to assay.
  • the tissue was cut into strips of 0.3 x 0.3 xl cm and suspended in organ chambers for isometric tension measurement. Tissues were incrementally stretched until optimal isometrtic tension for contraction was obtained. Once this was achieved, the tissues were contracted with phenylephine (7 x 10 "7 M) and once a stable contraction was achieved, the tissues were exposed to either dipyridamole or Example 1 (10 " to 3 x 10 " M) by cumulative additions to the chamber. At the end of the experiment papaverine (10 " M) is added to obtain maximal relaxation.

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Abstract

La présente invention concerne des inhibiteurs nitrosés et/ou nitrosylés de la phosphodiestérase, l'inhibiteur étant représenté par la formule NOn-PDE dans laquelle 'n' vaut 1 ou 2. Un tel inhibiteur de la phosphodiestérase peut être nitrosé ou nitrosylé par des sites tels que l'oxygène (condensation hydroxyl), le soufre (condensation sulfhydryl), le carbone et de l'azote. L'invention concerne également des compositions comprenant de tels composés associés à un excipient pharmaceutiquement admis. L'invention concerne par ailleurs une composition comprenant une quantité thérapeutiquement active d'un inhibiteur de la phosphodiestérase (inhibiteur PDE) qui peut être éventuellement substitué par un ou plusieurs groupes fonctionnels NO ou NO2 et un excédant molaire de un à dix fois d'un composé qui donne, transfère ou libère du monoxyde d'azote sous forme d'espèce chargée, en l'occurrence de nitrosinium (NO+) ou de nitroxyl (NO-), ou sous forme d'espèce neutre, en l'occurrence l'oxyde nitrique (NO.), qui stimule la production endogène d'EDRF. L'invention concerne en outre des compositions intégrant de tels composés dans un excipient pharmaceutiquement admis. L'invention concerne enfin un traitement dirigé contre l'impuissance masculine et consistant à administrer ces composés et des compositions à base de tels composés.
PCT/US1997/019870 1996-11-01 1997-10-31 Composes nitroses et nitrosyles inhibiteurs de la phosphodiesterase, compositions comprenant ces composes et utilisations correspondantes WO1998019672A1 (fr)

Priority Applications (22)

Application Number Priority Date Filing Date Title
CA002270118A CA2270118A1 (fr) 1996-11-01 1997-10-31 Composes nitroses et nitrosyles inhibiteurs de la phosphodiesterase, compositions comprenant ces composes et utilisations correspondantes
PCT/US1997/019870 WO1998019672A1 (fr) 1996-11-01 1997-10-31 Composes nitroses et nitrosyles inhibiteurs de la phosphodiesterase, compositions comprenant ces composes et utilisations correspondantes
EP97946871A EP0941086A4 (fr) 1996-11-01 1997-10-31 Composes nitroses et nitrosyles inhibiteurs de la phosphodiesterase, compositions comprenant ces composes et utilisations correspondantes
JP52161698A JP2001504457A (ja) 1996-11-01 1997-10-31 ニトロソ化およびニトロシル化ホスホジエステラーゼ阻害剤化合物、組成物及びその使用法
AU51962/98A AU722480B2 (en) 1996-11-01 1997-10-31 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/241,281 US6133272A (en) 1996-11-01 1999-02-01 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/247,321 US6177428B1 (en) 1996-11-01 1999-02-10 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/247,293 US6232321B1 (en) 1996-11-01 1999-02-10 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/247,323 US6316457B1 (en) 1996-11-01 1999-02-10 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/247,295 US6197782B1 (en) 1996-11-01 1999-02-10 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/247,320 US6197778B1 (en) 1996-11-01 1999-02-10 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/247,292 US6221881B1 (en) 1996-11-01 1999-02-10 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/247,322 US6172068B1 (en) 1996-11-01 1999-02-10 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/247,296 US6172060B1 (en) 1996-11-01 1999-02-10 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/347,426 US6211179B1 (en) 1996-11-01 1999-07-06 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/354,424 US6472425B1 (en) 1997-10-31 1999-07-16 Methods for treating female sexual dysfunctions
US09/387,727 US6331543B1 (en) 1996-11-01 1999-09-01 Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
US09/465,965 USRE37234E1 (en) 1996-11-01 1999-12-16 Nitrosated and nitrosylated phosphodiestrase inhibitor compounds, compositions and their uses
US09/941,691 US6462044B2 (en) 1996-11-01 2001-08-30 Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
US10/216,886 US6930113B2 (en) 1996-11-01 2002-08-13 Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
US10/694,183 US20040087591A1 (en) 1996-11-01 2003-10-28 Phosphodiesterase inhibitors and nitric oxide donors, compositions and methods of use
US11/819,514 US20080009498A1 (en) 1996-11-01 2007-06-27 Phosphodiesterase inhibitors and nitric oxide donors, compositions and methods of use

Applications Claiming Priority (3)

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US08/740,764 US5874437A (en) 1996-11-01 1996-11-01 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US08/740,764 1996-11-01
PCT/US1997/019870 WO1998019672A1 (fr) 1996-11-01 1997-10-31 Composes nitroses et nitrosyles inhibiteurs de la phosphodiesterase, compositions comprenant ces composes et utilisations correspondantes

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US08/740,764 Continuation-In-Part US5874437A (en) 1996-11-01 1996-11-01 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/145,142 Continuation-In-Part US5958926A (en) 1996-11-01 1998-09-01 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/241,281 Continuation-In-Part US6133272A (en) 1996-11-01 1999-02-01 Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US09/354,424 Division US6472425B1 (en) 1997-10-31 1999-07-16 Methods for treating female sexual dysfunctions
US11/819,514 Continuation-In-Part US20080009498A1 (en) 1996-11-01 2007-06-27 Phosphodiesterase inhibitors and nitric oxide donors, compositions and methods of use

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958926A (en) * 1996-11-01 1999-09-28 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
WO1999066933A1 (fr) * 1998-06-25 1999-12-29 New Millennium Pharmaceutical Research, Inc. Traitement de la dyserection par administration de sildenafil par voie nasale
WO2000035434A2 (fr) * 1998-12-14 2000-06-22 Cellegy Pharmaceuticals, Inc. Compositions et techniques de traitement de troubles anorectaux
EP1027054A1 (fr) * 1997-10-28 2000-08-16 Vivus, Inc. Apport local d'inhibiteurs de phosphodiesterases, dans le traitement du dysfonctionnement erectile
USRE37234E1 (en) * 1996-11-01 2001-06-19 Nitromed, Inc. Nitrosated and nitrosylated phosphodiestrase inhibitor compounds, compositions and their uses
WO2001070211A2 (fr) * 2000-03-23 2001-09-27 The Regents Of The University Of California Synergisme de la l-arginine et de l'inhibiteur de phosphodiesterase (pde)
US6331543B1 (en) 1996-11-01 2001-12-18 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
WO2002022127A1 (fr) * 2000-09-13 2002-03-21 Isis Innovation Limited Utilisation d"inhibiteurs de phosphodiesterase pour le traitement de trouble ano-rectal
US6472425B1 (en) 1997-10-31 2002-10-29 Nitromed, Inc. Methods for treating female sexual dysfunctions
WO2002087508A2 (fr) 2001-05-02 2002-11-07 Nitromed, Inc. Nebivolol nitrose et nitrosylate et ses metabolites, compositions et techniques d'utilisation
US6627632B2 (en) 1998-12-14 2003-09-30 Cellegy Pharmaceuticals, Inc. Compositions and methods for the treatment of anorectal disorders
EP1535611A2 (fr) * 1997-06-23 2005-06-01 Cellegy Pharmaceuticals, Inc Thérapie de conditions vasculaires par des microdoses de doneurs de NO
WO2007016677A2 (fr) 2005-08-02 2007-02-08 Nitromed, Inc. Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
CN1300114C (zh) * 2001-06-15 2007-02-14 安斯泰来制药有限公司 苯基吡啶甲酰哌嗪衍生物
US7253155B2 (en) 2001-10-05 2007-08-07 Combinatorx, Inc. Combinations for the treatment of immunoinflammatory disorders
WO2009135299A1 (fr) 2008-05-05 2009-11-12 Merck Frosst Canada Ltd. Dérivés de pipéridine substitués en 3,4 utilisés en tant qu'inhibiteurs de la rénine
US7799805B2 (en) 2005-05-27 2010-09-21 Actelion Pharmaceuticals Ltd. Piperidine carboxylic acid amide derivatives
WO2010144629A1 (fr) 2009-06-09 2010-12-16 Prolong Pharmaceuticals, LLC Compositions d'hémoglobine
US7875268B2 (en) 2004-04-06 2011-01-25 L'oreal S.A. Dimercaptoamides, compositions comprising them as reducing agents, and processes for permanently reshaping keratin fibers therewith
US7968720B2 (en) 2006-02-02 2011-06-28 Actelion Pharmaceuticals Ltd. Secondary amines as renin inhibitors
US8067414B2 (en) 2006-03-29 2011-11-29 Nicox S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
US8067464B2 (en) 2004-10-04 2011-11-29 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US8080553B2 (en) 2003-10-15 2011-12-20 Zalicus Inc. Methods and reagents for the treatment of immunoinflammatory disorders
US8138340B2 (en) 2004-08-25 2012-03-20 Actelion Pharmaceuticals Ltd. Bicyclononene derivatives
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WO2022022669A1 (fr) * 2020-07-30 2022-02-03 Biofront Therapeutics (Beijing) Co., Ltd. Composés à double fonction et leurs procédés d'utilisation
WO2023005180A1 (fr) * 2021-07-30 2023-02-02 Biofront Therapeutics (Beijing) Co., Ltd. Composés à double fonction et leurs procédés d'utilisation

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7067659B2 (en) * 2004-04-23 2006-06-27 Duke University Reactive oxygen generating enzyme inhibitor with nitric oxide bioactivity and uses thereof
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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4308278A (en) * 1978-01-11 1981-12-29 Gyogyszerkutato Intezet Anorexigenic 4-[(3,4-dialkoxyphenyl)alkyl]-2-imidazolidinone derivatives
US5196426A (en) * 1988-01-19 1993-03-23 Pfizer Inc. Calcium independent c amp phosphodiesterase inhibitor antidepressant
US5223504A (en) * 1989-12-27 1993-06-29 Laboratorios Almirall Sa Xanthine compounds and compositions, and methods of using them
US5254575A (en) * 1991-03-25 1993-10-19 Akzo N.V. 4-aryl-thiazole derivatives
US5340827A (en) * 1992-06-15 1994-08-23 Celltech, Limited Phenylcarboxamide compounds which have useful pharmaceutical activity
WO1995001338A1 (fr) * 1993-07-02 1995-01-12 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux benzamides a substituants fluoroalcoxy et leur utilisation comme inhibiteurs de la phosphodiesterase nucleotidique cyclique
US5426107A (en) * 1991-07-09 1995-06-20 Pfizer Inc. Pyrazolopyrimidinone antianginal agents
US5491147A (en) * 1992-10-23 1996-02-13 Celltech, Limited Tri-substituted phenyl derivatives and their use in pharmaceutical compositions and methods of treatment
US5545647A (en) * 1994-03-08 1996-08-13 Mitsubishi Chemical Corporation 3-phenylpyrrolidine derivatives

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4714705A (en) * 1986-07-07 1987-12-22 Ortho Pharmaceutical Corporation 4-nitrogen substituted isoquinolinol compounds having cardiotonic, phosphodiesterase fraction III inhibiting properties and/or renal vasodilating properties
GB8817651D0 (en) * 1988-07-25 1988-09-01 Smith Kline French Lab Chemical compounds
GB8928346D0 (en) * 1989-12-15 1990-02-21 Smith Kline French Lab Chemical compounds
GB9013750D0 (en) * 1990-06-20 1990-08-08 Pfizer Ltd Therapeutic agents
US5380758A (en) * 1991-03-29 1995-01-10 Brigham And Women's Hospital S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof
AU3237193A (en) * 1991-12-11 1993-07-19 Brigham And Women's Hospital S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof
US5728705A (en) * 1993-10-04 1998-03-17 The Trustees Of Columbia University In The City Of New York Method of inducing vasorelaxation to treat pulmonary hypertension
US6063407A (en) * 1995-02-16 2000-05-16 The General Hospital Corporation Treatment of vascular thrombosis and restenosis with inhaled nitric oxide
US5824669A (en) * 1996-03-22 1998-10-20 Nitromed, Inc. Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders
GB9608408D0 (en) * 1996-04-23 1996-06-26 Adams Michael A Treatment of erectile dysfunction

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4308278A (en) * 1978-01-11 1981-12-29 Gyogyszerkutato Intezet Anorexigenic 4-[(3,4-dialkoxyphenyl)alkyl]-2-imidazolidinone derivatives
US5196426A (en) * 1988-01-19 1993-03-23 Pfizer Inc. Calcium independent c amp phosphodiesterase inhibitor antidepressant
US5223504A (en) * 1989-12-27 1993-06-29 Laboratorios Almirall Sa Xanthine compounds and compositions, and methods of using them
US5254575A (en) * 1991-03-25 1993-10-19 Akzo N.V. 4-aryl-thiazole derivatives
US5426107A (en) * 1991-07-09 1995-06-20 Pfizer Inc. Pyrazolopyrimidinone antianginal agents
US5340827A (en) * 1992-06-15 1994-08-23 Celltech, Limited Phenylcarboxamide compounds which have useful pharmaceutical activity
US5491147A (en) * 1992-10-23 1996-02-13 Celltech, Limited Tri-substituted phenyl derivatives and their use in pharmaceutical compositions and methods of treatment
WO1995001338A1 (fr) * 1993-07-02 1995-01-12 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux benzamides a substituants fluoroalcoxy et leur utilisation comme inhibiteurs de la phosphodiesterase nucleotidique cyclique
US5545647A (en) * 1994-03-08 1996-08-13 Mitsubishi Chemical Corporation 3-phenylpyrrolidine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0941086A4 *

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE37234E1 (en) * 1996-11-01 2001-06-19 Nitromed, Inc. Nitrosated and nitrosylated phosphodiestrase inhibitor compounds, compositions and their uses
US6316457B1 (en) 1996-11-01 2001-11-13 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6221881B1 (en) 1996-11-01 2001-04-24 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6232321B1 (en) 1996-11-01 2001-05-15 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US5958926A (en) * 1996-11-01 1999-09-28 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6133272A (en) * 1996-11-01 2000-10-17 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6462044B2 (en) 1996-11-01 2002-10-08 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
US6172060B1 (en) 1996-11-01 2001-01-09 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6172068B1 (en) 1996-11-01 2001-01-09 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6177428B1 (en) 1996-11-01 2001-01-23 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6197778B1 (en) 1996-11-01 2001-03-06 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6197782B1 (en) 1996-11-01 2001-03-06 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6930113B2 (en) 1996-11-01 2005-08-16 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
US6211179B1 (en) 1996-11-01 2001-04-03 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6331543B1 (en) 1996-11-01 2001-12-18 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
EP1535611A2 (fr) * 1997-06-23 2005-06-01 Cellegy Pharmaceuticals, Inc Thérapie de conditions vasculaires par des microdoses de doneurs de NO
EP1535611A3 (fr) * 1997-06-23 2009-09-16 Strakan International Limited Thérapie de conditions vasculaires par des microdoses de doneurs de NO
EP1027054A1 (fr) * 1997-10-28 2000-08-16 Vivus, Inc. Apport local d'inhibiteurs de phosphodiesterases, dans le traitement du dysfonctionnement erectile
EP1027054A4 (fr) * 1997-10-28 2002-11-04 Vivus Inc Apport local d'inhibiteurs de phosphodiesterases, dans le traitement du dysfonctionnement erectile
US6472425B1 (en) 1997-10-31 2002-10-29 Nitromed, Inc. Methods for treating female sexual dysfunctions
US6200591B1 (en) 1998-06-25 2001-03-13 Anwar A. Hussain Method of administration of sildenafil to produce instantaneous response for the treatment of erectile dysfunction
WO1999066933A1 (fr) * 1998-06-25 1999-12-29 New Millennium Pharmaceutical Research, Inc. Traitement de la dyserection par administration de sildenafil par voie nasale
EP1109543A4 (fr) * 1998-09-01 2006-03-08 Nitromed Inc Inhibiteurs de la phosphodiesterase nitroses et nitrosyles, compositions et methodes d'utilisation
JP2002523450A (ja) * 1998-09-01 2002-07-30 ニトロメド インコーポレーテッド ニトロソ化およびニトロシル化されたホスホジエステラーゼ阻害剤、組成物および使用方法
AU773269B2 (en) * 1998-09-01 2004-05-20 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
EP1109543A1 (fr) * 1998-09-01 2001-06-27 Nitromed, Inc. Inhibiteurs de la phosphodiesterase nitroses et nitrosyles, compositions et methodes d'utilisation
WO2000012076A1 (fr) * 1998-09-01 2000-03-09 Nitromed, Inc. Inhibiteurs de la phosphodiesterase nitroses et nitrosyles, compositions et methodes d'utilisation
US6627632B2 (en) 1998-12-14 2003-09-30 Cellegy Pharmaceuticals, Inc. Compositions and methods for the treatment of anorectal disorders
WO2000035434A3 (fr) * 1998-12-14 2000-11-30 Cellegy Pharma Inc Compositions et techniques de traitement de troubles anorectaux
EP1143956A3 (fr) * 1998-12-14 2001-12-12 Cellegy Pharmaceuticals, Inc Compositions et techniques de traitement de troubles anorectaux
WO2000035434A2 (fr) * 1998-12-14 2000-06-22 Cellegy Pharmaceuticals, Inc. Compositions et techniques de traitement de troubles anorectaux
JP2002542147A (ja) * 1998-12-14 2002-12-10 セレジィ ファーマシューティカルス， インコーポレイテッド 肛門直腸障害の処置のための組成物および方法
US6476037B1 (en) 2000-03-23 2002-11-05 The Regents Of The University Of California L-arginine and phosphodiesterase (PDE) inhibitor synergism
WO2001070211A3 (fr) * 2000-03-23 2002-08-08 Univ California Synergisme de la l-arginine et de l'inhibiteur de phosphodiesterase (pde)
WO2001070211A2 (fr) * 2000-03-23 2001-09-27 The Regents Of The University Of California Synergisme de la l-arginine et de l'inhibiteur de phosphodiesterase (pde)
WO2002022127A1 (fr) * 2000-09-13 2002-03-21 Isis Innovation Limited Utilisation d"inhibiteurs de phosphodiesterase pour le traitement de trouble ano-rectal
WO2002087508A2 (fr) 2001-05-02 2002-11-07 Nitromed, Inc. Nebivolol nitrose et nitrosylate et ses metabolites, compositions et techniques d'utilisation
CN1300114C (zh) * 2001-06-15 2007-02-14 安斯泰来制药有限公司 苯基吡啶甲酰哌嗪衍生物
US7915265B2 (en) 2001-10-05 2011-03-29 Zalicus Inc. Combinations for the treatment of immunoinflammatory disorders
US7253155B2 (en) 2001-10-05 2007-08-07 Combinatorx, Inc. Combinations for the treatment of immunoinflammatory disorders
US8080553B2 (en) 2003-10-15 2011-12-20 Zalicus Inc. Methods and reagents for the treatment of immunoinflammatory disorders
US7875268B2 (en) 2004-04-06 2011-01-25 L'oreal S.A. Dimercaptoamides, compositions comprising them as reducing agents, and processes for permanently reshaping keratin fibers therewith
US8138340B2 (en) 2004-08-25 2012-03-20 Actelion Pharmaceuticals Ltd. Bicyclononene derivatives
US8067464B2 (en) 2004-10-04 2011-11-29 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US7799805B2 (en) 2005-05-27 2010-09-21 Actelion Pharmaceuticals Ltd. Piperidine carboxylic acid amide derivatives
WO2007016677A2 (fr) 2005-08-02 2007-02-08 Nitromed, Inc. Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
US7968720B2 (en) 2006-02-02 2011-06-28 Actelion Pharmaceuticals Ltd. Secondary amines as renin inhibitors
US8067414B2 (en) 2006-03-29 2011-11-29 Nicox S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
US8846674B2 (en) 2006-03-29 2014-09-30 Nicox, S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
WO2009135299A1 (fr) 2008-05-05 2009-11-12 Merck Frosst Canada Ltd. Dérivés de pipéridine substitués en 3,4 utilisés en tant qu'inhibiteurs de la rénine
US8889714B2 (en) 2008-05-05 2014-11-18 Actelion Pharmaceuticals Ltd. 3,4-substituted piperidine derivatives as renin inhibitors
WO2010144629A1 (fr) 2009-06-09 2010-12-16 Prolong Pharmaceuticals, LLC Compositions d'hémoglobine
EP3266463A1 (fr) 2009-06-09 2018-01-10 Prolong Pharmaceuticals, LLC Compositions d'hémoglobine
CN113767104A (zh) * 2020-07-30 2021-12-07 百放英库医药科技(北京)有限公司 双功能化合物及其使用方法
WO2022022669A1 (fr) * 2020-07-30 2022-02-03 Biofront Therapeutics (Beijing) Co., Ltd. Composés à double fonction et leurs procédés d'utilisation
CN113767104B (zh) * 2020-07-30 2023-08-22 百放英库医药科技(北京)有限公司 双功能化合物及其使用方法
US11987556B2 (en) 2020-07-30 2024-05-21 Biofront Therapeutics (Beijing) Co., Ltd. Dual-functional compounds and methods of use
WO2023005180A1 (fr) * 2021-07-30 2023-02-02 Biofront Therapeutics (Beijing) Co., Ltd. Composés à double fonction et leurs procédés d'utilisation

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EP0941086A1 (fr) 1999-09-15
AU722480B2 (en) 2000-08-03
AU5196298A (en) 1998-05-29
EP0941086A4 (fr) 2000-07-12
CA2270118A1 (fr) 1998-05-14

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