CA2422787A1 - C-nitroso compounds and use thereof - Google Patents

Abstract

A C-nitroso compound having a molecular weight ranging from 225 to 1,000 (from 225 to 600 for oral administration) on a monomeric basis wherein a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25, is useful as an NO donor. When the compound is obtained from a carbon acid with a pKa less than about 10, it provides vascular relaxing effect when used at micromolar concentrations and this activity is potentiated by glutathione to be obtained at nanomolar concentrations. When the compound is obtained from a carbon acid with a pKa ranging from about 15 to 20, vascular relaxing effect is obtained at nanomolar concentrations without glutathione. In another embodiment, a biocompatible polymer incorporates a C-nitroso moiety.

Description

C-NITROSO COMPOUNDS AND USE THEREOF
Technical Field The invention relates to C-nitroso compounds which are therapeutically active at low concentrations as NO donors.
Back Crround of the Invention NO donors are known to be useful for therapeutic utility, e.g., to prevent restenosis following augioplasty (Groves, P., et al., Cardiovascular Research 26, 615-619 (1992)), to inhibit platelets to prevent coagulation and thrombus formation (Crroves, P., et al., Circulation 87, 590-597 (1993)) and to treat angina (Knight, et al., Circulation 95, 125-132 (1997)). NO
donors are considered to have additional therapeutic utility in cancer, killing microbes and viruses, relaxing airways and intestinal smooth muscle (e.g., for treating asthma and esophageal spasms), in promoting erectile function and in treatment ofheart failure and urinary incontinence.
NO donors are described in '2VIethods in Nitric Oxide Research," edited by Feelisch, M., and Stamler, J. S., John Wiley & Sons, New York, 1996 at pages 71-115. These NO donors are O-nitroso and S-nitroso compounds, and C-nitroso compounds that are excluded from the invention herein.
Twenty-two additional C-nitroso compounds are desci~bed in Rehse, K., et al., Arch.
Pharm. Pharm. Med. Chem. 331, 104-110 (1998). These compounds are oflowmolecular weight and are not water-soluble and were shown to be weakly active. Other C-nitroso compounds are described in Rehse, K., et al., Arch. Phamn. Pharm Med. Chem.
331, 79- 84 (1998); these are vitro-nitroso compounds and the specific compounds mentioned are excluded from the invention herein.
Other C-nitroso compounds which are old are 3-methyl-3-nitroso-2,4-pentanedione and 3-ethyl-3-nitroso-2,4-pentanedione. These compounds and their synthesis are described in Sklyar, Yu. E., et al., Khimiya Geterotsiklicheskikh Soediuenii 5, 70-73 (1969). These comp ounds are of low molecular weight and do not meet the definition of water solubility set forth hereinafter.

Sunvnary of the Invention It has been discovered in a first embodiment herein that certain C-nitroso compounds of higher molecular weight than have previously been prepared, especially those that are water-soluble, are therapeutically active as NO donors at nanomolar concentrations, in some cases when used alone and in some cases in the presence of glutathione.
The C-nitroso compounds of the first embodiment herein. have a nitroso group attached to a tertiary carbon. Otherwise there is an essentially irreversible tautomerization to the corresponding oxime which is generally not active. It has been discovered herein that the nitroso group being attached to a tertiary carbon is important for good activity.
The C-nitroso compounds ofthe first embodiment herein have a molecular weight ranging from about 225 to about 1,000 on a monomeric basis. The high activity obtained for compounds ofthis molecular weight is considered to be surprising and means that many drugs that are now being used can be converted to C-nitroso compounds providing not only the therapeutic effect of the starting drug but also advantages provided by nitroso group including relaxation effect and other advantages as described later.
The C-nitroso compounds of the first embodiment herein are obtained by nitrosylation of a carbon acid having a pica less than about 25. C-nitroso compounds derived from carbon acids with lower acidities (higher pica values) will not act as useful donors of NO.
Thus, the invention of the first embodiment in its broad aspects is directed to a C-nitroso compound having a molecular weight ranging from about 225 to about 1,000 on a monomer basis wherein a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pica less than about 25.
The C-nitroso compound is preferably water-soluble and preferably contains carbon alpha to nitrosylated carbon which is part of a ketone group.
In one subgenus, the C-nitroso compound is obtained by nitrosylation of a carbon acid having a pKa less than 10. Compounds of this subgenus, when used alone, have NO donating and relaxation providing activity when used at. mice omolar concentrations.
However, it has been discovered herein that this activity is potentiated by glutathione, so compounds of this subgenus, when administered with or to react with glutathione, are therapeutically active (to provide NO donating and relaxation effects) when used at nanomolar concentrations. Thus, an embodiment herein is directed to a method of treating a patient with such C-nitroso compound at nanomolar (e.g., from 0.1 to 900 nanomolar) concentrations, together with glutathione to provide NO donating and relaxing effect, where the patient is one in need of NO donating and/or relaxing effect and/or is in need of nitrosoglutathione.
In another subgenus, the C-nitroso compound is obtained by nitrosylation of a carbon acid having a pKa ranging from about 15 to about 20. It has been found in this case that the compound is therapeutically active and provides nitrosylating activity and relaxing effect when used at nanomolar concentrations without potentiation and that glutathione inhibits the activity of the compound.
It has been discovered herein that C-nitroso compounds of the invention herein can be obtained by nitrosylating the tertiary carbon atom of a conventional drug if that drug constitutes a carbon acid having a pKa less than 25 or can be converted to a carbon acid having a pKa less than 25 and will provide a C-nitroso compound meeting the aforedescribed molecular weight limitations. The resulting C-nitroso compounds retain the activity of the drug and additionally provide the relaxation effect associated with NO and can provide other beneficial effect as described below. The conventional dxugs include, for example, nonsteroidal anti-inflammatory drugs, GOX-2 inhibitors, analgesic drugs, antianginal drugs, antihypertensive drugs, diuretic drugs, ACE inhibitors, antihypercholesterolemic/antihyperlipoproteinemic chugs, calcium channel blockers, antacids, bronchodilators, NlVILIA antagonist/skeletal muscle relaxant drugs, autiproliferation/tubulin binding agents, antitubercular agents, CETP inhibitors, SOD mimemetics, and xanthine oxidase inhibitors.
It has been discovered herein that when the conventional chug is a nonsteroidal anti-inflammatory chug that is a COX-1 and a COX-2 inhibitor, the resulting C-nitroso compound will function as a COX-l and COX-2 inhibitor without the deleterious effects associated with COX-1 inhibition but with the advantages associated with COX-l and COX-2 inhibition. In particular, COX-1 mediates production of thromboxane which mediates platelet aggregation thereby providing a deleterious effect; inhibition of COX-1 reverses this effect. This reversal is reinforced by the C-nitroso nonsteroidal anti-inflammatory drugs herein. On the other hand, COX-1 inhibitors inhibit production ofprostaglandins which protect against ulcers; the NO
associated with the nonsteroidal anti-inflammatory drugs herein protects against this deleterious side effect. While the COX-1 inhibiting effect that mediates stomach attack is _q partly related to a deficiency of NO, there is an NO beneficial effect that may be COX-1 independent that more than negates the detrimental effect of inhibition of COX-1 production ofprostaglandins. Thus, the C-nitroso nonsteroidal anti-inflammatory COX-1/COX-inhibitors herein provide an advantage over selective inhibitors of COX-2 in also providing the advantageous effects associated with COX-1 inhibition and other NO beneficial effects.
Furthermore, C-aitroso selective COX-2 inhibitors provide not only the advantages of COX-2 inhibition but also some of the advantages associated with COX-1 inhibition.
Furthermore, the NO in C-nitroso COX inhibitors potentiates the alleviating effect of COX
inhibitors on urinary incontinence.
Dimeric 2-[4'-(a-nitroso)isobutyrylphenyl]propionic acid has been synthesized herein and is obtained by C-nitrosylation of ibuprofen modified to have a lower carbon acid pKa. It represents a C-nitroso compound herein obtained by nitrosylation of a carbon acid having a pKa ranging fiom about 15 to about 25 and is therapeutically active without glutathione when used at nanomolar concentrations.
Thus, one embodiment herein is directed to a method oftreating a patient with an inflammatory or painful disorder composing administering to said patient a tlierapeutically effective (inflammation and/or pain relieving) amount of a C-nitroso compound ofthe instant invention which is obtained by nitrosylation of the tertiary carbon of a conventional nonsteroidal anti-inflammatory drug which has a carbon acid pKa ranging from about 15 to about 25, e.g., 15 to about 20, or such modified to have this carbon acid pKa where the C-nitroso compound preferably is dimenc 2-[4'-(a-nitroso)isobutyrylphenyl]propionic acid or an aqueous solution thereof.
It has also discovered herein that the pKa of a carbon acid of a compound may be used to target an NO group to provide nitrosylated compound. This is not the case in preparing other classes ofNO donor, e.g., -ONO and -SNO NO donors.
In addition, there has been discovered a new class of compounds, that are C-nitroso compounds and contain the moiety -C-N(O)X-where-X is S, O or NR and protonated derivatives thereof, which are useful in promoting conupound lifetime and providing modulated bioactivity. These compounds have a molecular weight ranging, for example, from about 100 to about 1,000 on a monomel~c basis. These compounds are referred to as C-nitroso compounds of the second embodiment herein. The compounds ofRehse, K. et al., Arch. Pharm. Pharm. Med. Chem. 331, 79-84 (1998) are excluded from the new class of compounds herein.
Shinmura, K., et al., PNAS 97, 10197-1002 (2000) shows COX-2 mediates cardioprotective effects of ischemic preconditioning, in particular the late phase of ischemic preconditioning (in this case the heart is made ischemic briefly to protect against a subsequent ischemia that is much more severe). Thus COX-2 inhibitors interfere with this cardioprotective effect. However, in the case of C-nitroso COX-2 inhibitors herein the NO
replaces the COX-2 mediation that is lost so there is a special benefit. This is also a similar benefit obtained with O-nitroso and S-nitroso COX-2 inhibitors. Thus, one embodiment herein is directed to COX-2 inhibitors where a tertiary carbon or an oxygen or sulfur is vitro sylated.
Other embodiments herein are directed to biocompatible polymers incorporating C-nitroso moiety derived from a carbon acid with a pKa less than 25 having a weight average molecular weight (determined by light scattering) ranging from 50,000 to 500,000, to medical devices coated with this polymer, to a method for the prophylaxis of a patient who is at risk for coagulation or thrombus formation or microbial or viral infection, e.g., a patient having or who is at risk for restenosis, compi~sing contacting tissue in the area that is at risk with this polymer.
As used herein, the term "carbon acid" means compound that contains a CH group which disassociates to C- and Ii+.
As used herein, the tei7n 'water-soluble" means dissolves in water at least to provide a concentration of 1 micromolar.
As used herein, the term "conventional drug" means therapeutic agent without NO
donor elect.
As used herein, the teen. "ketone group" means carbonyl group.
As used herein, the tern "electron withdrawing substituent" means atom or group where the connecting atom or group is more electronegative than hydrogen.

Brief Description of the Dr awings Figs. 1-10 are tracings of tension (force) versus time with concentrations of compound also shown for particular times and show results of Example II.
Fig. 1 is directed to results with compound (129a) described hereinafter.
Fig. 2 is directed to results with C-nitroso-methylmalonic acid.
Fig. 3 is directed to results with C-nitrosobenzene.
Fig. 4 is directed to results with C-nitrosophenol.
Fig. 5 is directed to results with the C-nitrosoketoibuprofen synthesized in Example I.
Fig. 6 is similar to Fig. 5 but with indications of presence of dimer and more denotations of concentration.
Fig. 7 is directed to results for the combination of the C-nitrosoketoibuprofen and 100 ~cM glutathione.
Fig. 8 similar to Fig. 5 but with another concentration denoted.
Fig. 9 is directed to results for 3-methyl 3-nitroso-2,4-pentanedione, including potentiation with glutathione (GSII).
Fig. 10 is directed to results for 2-methyl-2-nitrosopropane.
Figs. 2, 3, 4, 9 and 10 are directed to results with reference compounds although Fig. 9 is relied on for showing the potentiation effect that occurs in one embodiment of the invention.
Figs. 1 and 5-8 are directed to results with C-nitroso compound of embodiments of the invention.
Detailed Description We tutu now to the embodiment of the first embodiment of the invention, which is directed to a C-nitroso compound having a molecular weight ranging from about 225 to about 1,000 on a monomer basis wherein a nitroso group is attached to a tertiary carbon which is obtained by nitrosylation of a carbon acid having a plea less than about 25.
The molecular weight typically ranges fiom about 225 to about 600 on a monomer basis for oral administration.
We tutu now to the subgenus where the C-nitroso compound is obtained by nitrosylation of a carbon acid having a pKa less than about 10. When used alone, this compound displays activity (NO donating and/or relaxation activity) when used at micromolar _'j_ concentrations and will nitrosylate the modestly nucleophilic thiol of a cysteine residue or a low molecular weight derivative (e.g., glutathione). The native activity is presumably mediated by nitrite derived fiom nitrosylation of water. This mode of action shows little if any specificity and is very weak. As indicated above, it has been discovered in the course of this invention that this activity is potentiated by the presence of glutatbione.
This potentiation is roughly 1,000-fold.
We tm.~n now to the subgenus where the C-nitroso compound is obtained by nitrosylation of a carbon acid having a pica ranging from about 15 to about 20. These C-nitrosotliiols will not nitrosylate glutathione but will selectively nitrosylate highly nucleophilic thiols found in protein targets. Thus, highly nucleophilic thiols can be targeted by the use of these C-nitroso compounds.
One class of C-nitroso compounds of the first embodiment is made up of C-nitroso compounds having a molecular weight ranging from 225 to 1,000, e.g., 225 to 600, on a monomeric basis, where a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25, where a substituent Q is attached to the tertiary carbon and consists of a chain moiety containing 1 to 12 chain atoms consisting of 1 to 10 carbon atoms, 0 to 2 nitrogen atoms, and 0 to 2 oxygen atoms covalently bonded to a cyclic moiety which is monocyclic, bicyclic, tricyclic, icetracyclic or pentacyclic, and contains 5 to 24 ring atoms consisting of 2 to 20 carbon atoms, 0 to 4 nitrogen atoms, 0 to 1 oxygen atoms and 0 to 1 sulfur atoms. The "chain atoms" are counted by counting the atoms connecting the tertiary carbon atom and the cyclic moiety, and exclude hydrogen and other substituents on the chain. The '~-iug atoms" are counted by counting the atoms forming the ring(s), and exclude hydrogen or other substituents on the ring. Besides the substituent Q, the tertiary carbon is bonded to the substituents Q' and Q". If Q does not contain an electron withdrawing group including or on carbon directly bonded to the tertiary carbon or even if it does, at least one of the groups Q' and Q" preferably contains an electron withdrawing atom or group including or on carbon directly bonded to the tertiary carbon, e.g., a ffuonne atom, carbonyl group per se or as part of an ester group, vitro, cyanide, CF3 or SOZR where R
comprises Cl-C6 alkyl or C6 C2o aryl. So far as Q' and Q" are concerned, any atoms downstream of carbon alpha to the tertiary carbon are unci~tical. Examples of Q' and Q" are Rl, RZ, R1C(O)-, RzC(O), R1CH2C(O)-, RZCHZC(O)-, -C(O)COON, methyl, -COZMe, -CF3, -g-and -CN, where R, and RZ are selected from the group consisting of C1-C6 alkyl and C6-CZo aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated, i.e., substituted with sulfate, and/or phosphorylated, i.e., substituted with phosphate.
Another class of C-nitroso compounds of the first embodiment is made up of C-nitroso compounds having a molecular weight ranging from 225 to 1,000, e.g., 225 to 600, on a monomeric basis, where a nitroso gTOUp is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25, where the tertiary carbon is a ring atom in a cyclic moiety which is monocyclic, bicyclic, tricyclic, tetracyclic or pentacyclic, and contains from 5 to 24 ring atoms consisting of 2 to 20 carbon atoms, 0 to 4 nitrogen atoms, 0 to 1 oxygen atoms and 0 to 1 sulftu atoms where the ring atoms are counted by counting the atoms fomning the ring(s), and exclude hydrogen or other substituent on the ring.
In this case, two of the carbons attached to the tertiary carbon are part of the ring structure of the cyclic moiety and the other carbon attached to the tertiary carbon is part of a substituent which preferably contains an electron withdrawing atom or group (e.g., as exemplified above), including or on the carbon directly bonded to the tertiary carbon and any atoms downstream of said other carbon alpha to the tertiary carbon are uncutical.
Still another class of C-nitroso compounds of the first embodiW ent is made up of C-nitroso compounds having a molecular weight ranging from 225 to 1,000, e.g., 225 to 600, on a monomeric basis, where a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25, where the C-nitroso compound is acyclic where at least one substituent on the tertiary carbon contains from 4 to 20 carbon atoms and that substituent and/or one or both of the other substituents on the tertiary contain electron withdrawing atom or group (e.g., as exemplified above), including or on carbon directly bonded to the tertiary carbon and any atoms downstream, except as recited and except as necessary to provide the recited molecular weight, are uncritical.
The C-nitroso compounds described in "Methods in Nitric Oxide Research,"
edited by lFeelisch, M. and Stamler, J. S., John Wilen & Sons, New York ( 1996) are excluded from the invention herein.

-The C-nitroso. compounds described in Rehse, K., et al., Arch. Pharm. Pharm.
Med.
Chem. 331, 104-110 (1998) and Rehse, K., et al., Arch. Pharm. Phamn. Med.
Chem., 331, 79-84 (1998) are excluded from the C-nitrosothiols of the invention.
Also excluded from the C-nitrosothiols of the invention are the C-nitrosodiones described in Sklyar, Yu. E., et al., Khimiya Geterotsiklicheskikh Soedinenii 5,70-73 (1969).
The potentiation effect of glutathione on C-nitroso compounds derived from carbon acids with pKa's less than 10 is new and is one embodiment of the invention herein.
The C-nitrosylated compounds herein, when isolated, form dimers which are solid and very stable and therefore the compounds herein have long shelf lives and are capable of being stored at ambient temperatures in the presence of oxygen and light for months.
While the dimers are inactive, they form monomers in water which are active. They can be administered as aqueous solutions for instant activity. They also can be administered as dimers to provide sustained release effect as the dimer dissolves in the body. Thus, the dimers herein have been discovered to promote compound lifetime and modulate compound bioactivity, and the release rates are not directly related to the activity of these compounds. The dimerization and greater stability are greatly favored for a-acyl C-nitroso compounds; hence the preference above for C-nitroso compounds where carbon alpha to the nitrosylated carbon is part of a ketone group.
As indicated above, C-nitroso compound herein is obtained by i~itrosylating a tertiary carbon atom of a conventional drug or of a conventional drug modified to modify the carbon acid pKa thereof. ' The carbon acid pKa can be reduced, for example, by converting a carbon alpha to tertiary carbon to be nitrosylated to a ketone group or by the addition of other electron withdrawing substituent (e.g., fluorine, vitro, cyanide, CF3 or SOZRwhere R is as defined above).
Various embodiments where C-nitroso compound herein is obtained by nitrosylating tertiary carbon atom of a conventional drug or a conventional drug modified to modify the carbon acid pKa thereof include C-nitroso compound having a molecular weight ranging from 225 to 600 on a monomeric basis where a nitroso group is attached to a tertiary which is obtained by nitrosylation ofthe conventional drug (e.g., a nonsteroidal anti-inffammatoiy drug, a COX-2 inhibitor, an analgesic chug, an antianginal chug, an antihypertensive drug, a diuretic drug, an ACE inhibitor, an antihypercholesterolemic/antihyperlipoproteinemic chug, a calcium channel blocker, an antacid, a bronchodilator, an NMDA antagonist/skeletal muscle relaxant -lo-drug, an antiproliferation/tubulin binding agent drug, a CETP inhibitor, and SOD mimetic or a xanthine.oxidase inhibitor) having a carbon acid pKa ranging from about 15 to about 25, e.g., about 15 to about 20, or said drug modified to have a carbon acid pKa ranging from about 15 to about 25, e.g., about 15 to about 20.
When C-nitroso compound is obtained from a conventional drug, it retains the functionality of the drug and also provides NO donating relaxing effect.
Sometimes this results in a synergistic effect. For example, when the C-nitroso compound is derived from a nonsteroidal anti-inflammatory drug which inhibits COX-1 as well as COX-2, the result is a COX-1 inhibitor with the advantages but not the disadvantages of COX-1 inhibition by conventional NSAIDS and also a COX-2 inhibitor with the advantages thereof and wherein certain beneficial effects (e.g., amelioration of urinary incontinence or mediating preconditioning) may be potentiated or newly endowed. A compound synthesized herein was derived from ibuprofen which inhibits COX-1 as well as COX-2. In the synthesis, the ibuprofen was first converted to lcetoibuprofen to lower the pica to be within 15 to about 20.
The nitrosylated compound, a nitrosoketoibuprofen, isolated as dimeric 2-[4'-(a-nitroso)isobutyrylphenyl]propionic acid, provides the advantages of COX-1 and inhibition without pathological effects typically associated with COX-1 inhibition.
Below are listed conventional drugs and C-nitroso compounds of the first embodiment of the invention derived therefrom. In the description of the compounds below, the term "substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated" is often used; this phrase means substituted with amino, hydroxyl, carboxy, sulfate and/or phosphate. Whenever an anion is set forth without depiction of a balancing cation, the balancing canon is present and is selected from the group consisting of Ff-, Na+, I~+, Li+, Cap and tetralkylammonium.
The analgesic acetylsalicylic acid has the formula C0~
I IO

C-Nitroso compounds ofthe invention derived from acetylsalicylic acid include, for example:
Co2 o o (1) O R

ON R~
O
\ O R~ R2 \,.~~~ NO
O
O O
I o%~~~ No \ O R1 R2 O II . (3) O
In (1), (2) and (3), Rl, and RZ are selected from the group consisting of C~
C6 all~yl and C6 CZO aryl and substituted derivatives ofthese, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated .

,The antiangin.al propanalol has the fonnttla O~' N
ON N
i I w i C-Nitroso compounds of the invention derived from propanalol include, for example:

NO
O~~ H~°~P, OH O ~ 2 R;~R~ NO
O~ H ~~'~~ R2 .
I ~ OH -O 0 i OH H
o O
i ~ = CHI, O, NN

In (4), (5) and (6), R1, RZ and R3 are selected from the group consisting of C,-C6 allcyl and C6-CZO aryl and substituted derivatives of these, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The antianginal nadolol has the fomnula:
O~~ N
HO ~ OH H
HO
C-Nitroso compounds ofthe invention derived fromnadololinclude, for example:
R3 Rø o o~~ ~><~~ N o HO ~ OH p Ri R?
HO I
R3 R~ R5 NO
O~ H%~1TI~ R1 HO ~ OH O O
HO

O~
R10 ' off H
R20 ~ i. .
where Ri, R _ H 0 Ri R2 0 0 R
0 Ri NO 2 In (7), (8) and (9), Rl, Rz, R3, R4 and RS are selected fiom the group consisting, of Ci C6 allzyl and C6-CZo aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl andlor carboxy and/or Which are sulfated and/or phosphoiylated.
The antianginal and heart failure protective carvedilol has the formula:

O~N-'~.0 \ OH H
\ .%lN ~ , H
C-Nitroso compounds of the invention derived fiom caivedilol include, for example:
OCH~
O~~ RIO
OR /
(lo) N
R
O O
when a R = H, 0 R~ R2 . ~~ ~'~ N O ' ~~r~~ R2 O R~

,In (10), R1 and RZ are selected from group consisting of C1-C6 alkyl and C6 CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated.and/or phosphorylated.
The antihypertensive prazosin has the formula:
O O
H3C0 ~ N ~ N ~ /
y H~CO ~ ~ N
NH., C-Nitroso compounds of the invention derived from prazosin which are exemplary of alpha adrenergic receptor agonists useful to treat erectile dysfunction, include, for example:
O~ O
~' N 1 /
H3C0 , NYN J (11) H3CO ~ ~ N O
HN ~ J~~R2 NO

a o H3C0 ~ N ~N
H C ~ I YNJ (12) a O ~N O
HN~J
R~ NOR2 -where O O
~N 1/
RIO ~ NYNJ , R O ~ i 'N (13) NHS O R~ R2 Ri, R2 = CH3, \\JJ II NO
OO O ' \~~~~ Rz R~ NO
In (11), (12) and (13), Rl and RZ are selected fiom the group consisting of Cl-C6 all~yl and C6 CZO aryl and substituted derivatives thereof e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The antihypey-tensive tinolol has the formula:
i~l~~
~N
~N O~N
OH H
D
C-Nitroso compounds of the invention derived from tinolol include, for example:
,S, N~N o ( 14) ~N O~N%~yN0 . . N'S~N . , R~ NO
O~ N ~~~~ R2 . ( 15 ) . OH H O. O
N~S~N
~N O~H (16) OJ
O ~O

,S~
N /N . , N o (17) R~
~O
'O
~2 N.S.
. .~N
y ~
0 N._/ OH H (18) O
NO
,s, N" , N
j--N O~ N
OH N
O N

ON O
(19) In compounds (14); (15), (16), (17), (18) and (19), R1 and RZ are selected fiomtlie group consisting of C,-C6 all~yl and C6-CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxy and/or carboy and/or which are sulfated and/or phosphoiylated.
The antihypertensive metoprolol has the formula:
~NH~
~ o~
o ~ .

C-Nitroso compounds of the invention derived from metoprolol include, for example:
O NO
~__~~R (20) \\ 1 ~ ~NH 0 R2 O / O OH

CIO Rz O
'--NM 0 (21) off.-off NH~ .
O
O ~..J
Hs0 (22) R =_ O R1 R2 0 O
where \\J~~NO ' ~
p \\/J~~z NH~
~ ~ O
(23) R

where R =
'"~NO ~ ~'~'~R
O ' R~ NO z In compounds (20), (21), (22) and (23), Rl and RZ are selected from the group consisting of Cl-C6 alkyl and C6 Czo aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphozylated.
The antihypertensiee pindalol has the formula:
H
N

'OH
~NH
C-Nitroso ~con~pounds of the invention derived fiom pindalol include, for example:
H
N
(24) O
~OR
~NH
where ~rR= ORi R2 0 O
~~~~~NO , ~~~~~R
0 R~ NO z H
N
(~5) OH
NH
O
'O
ON R~
Rz H
i ~ N
(26) O
~OH
NH

ON 'O
Rz O
(27) O
.OH
NH

-.22-(28) O
~OH
JNH
In (24), (25), (26), (27) and (28), R1 and RZ are selected from the group consisting of Cl-C6 alkyl and C6 CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The antihypertensive labetalol has the formula:
O OH H
.HzN > I N w I
HO
C-Nitroso compounds of the invention derived fiom labetalol include, for example:
(29) (30) HN
(31) where R~,Rz,R3 ' H . 0 R1 Rz .
\\~~NO ' O

\'~~~R2 R~ NO
O OH (32) i HzN ~ I N QTR
HO ~

o O
Where ~~ R1~ ~R2 R ~~!~~NO ' R~ NORz ~ ~O
In (29), (30), (31) and (32), Rl and R~ are selected fiom the group consisting of Cl-C6 allcyl and C6 Czo aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The diuretic triamterene has the formula:
H2N~N NY.NH2 .~~ N
H5 \N

C-Nitroso compounds of the invention derived from triampterene include, for example:
RHN N N NHR
(33) ~N.
NHR
where R ' O R1 R2 O O
\~J~NO ' 0 ~~~%~ Ra_ Ri NO

,In (33), Rl and RZ are selected from the group consisting of Cl-C6 alkyl and C6 CZp aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The diuretic furosemide has the formula:

H ~
N

CI
C-Nitroso compounds of the invention derived from fixrosemide are uniquely useful in treating heart failure in combining diuretic and vasodilator functions and include, for example:
~z NO
O' Rt O
(34) O
~ N ~ /

CI
NO
R~ O

O 0 (35) w Cl ON 'O

N
NH2S02 , CI
NO
O Rt H02C O O~ (37) I

C!
In (34), (35), (36) and (37), R1 and R~ are selected fiomthe group consisting of C1-C6 alkyl and C6-CZO aryl and substituted derivatives thereofa e.g., substituted with amino, hydroxyl and/or carboxy and/ox which are sulfated and/or phosphorylated.
The ACE inhibitor enalapril. has the formula:
Et02C H020~s/~
N
i :.~~ H

C-Nitroso compounds of the invention herein derived from enalapril have improved antianginal effect when used to lower blood pressure and improved antiplatelet activity and include, for example:
Et02C H02C,, N N
O O (3 8) . O RT
NO

Rz O _ ON O
Rj O O H02C,, ~ (39) °' NN
O
NO
RW
R O
z O O H02C,, (40) \ H I
O °

EfOzC H02C,, i _ N N~ (41) \ ) O
O
R~

In (38), (39), (40) and (41), R1 and RZ are selected from the group consisting of C1-C6 alliyl and C6-CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or caxboxy and/or which are sulfated aud/or phosphorylated.
The ACE inhibitor. r ampiril has the formula:
~t02C HOC,,, l \ H~N
O
C-Nitroso compounds of the invention hereir<~ deuved from rairipiril~include, for example:
R NO
a 0 O' O H02C,,,, \ I N N
O

Rz O
ON
O
O
O
O HOzC~, H N
O
(43) EtOzC F-tO2C,,~
N
\ O O . (44) O Ri NO

Et02C H02C,, \ I O N N
O (45) ON O

In (42), (43), (44) and (45), R, and RZ are selected from the group consisting of Ci-C6 alkyl and C6 CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydro~.yl and/or carboxy and/or which are sulfated and/or phosphorylated.

The antihypercholesterolemic/antihyperlipoprotein.emic lovastatin has the formula:
HO O
O
HaC ' 1 0 H

,,, i-f3C' C-Nitroso compounds ofthe invention herein deritved from Tovastatin include, for example:
0 0 .
R2~~0 O
ON R~
O ,, 0 (46) H3C~ _ H

HsC,, R~ R2 O O 0 ON~~
O
O
HsC~O H (47) H3C CHs ,. / /
H3C, .

HO O

ON ~~~0 H . (48) R2 'R~ I0 CH3 H C

Oi'~ R1 Rz 0 (4.9) O
/ '/
,,, ~-130 .
In (46), (47), (4~) and (49), Rl and RZ are selected from the group consisting of Cl-C6 allcyl and C6 CZo aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated andlor phosphorylated.
The antihypercholesterolemic/autihyperlipoproteinemic pravastatin has the formula:
,,OH
O
H30~0 H3G j, C-Nitroso compounds of the invention herein derived fiom pravastatin include, for example:
Na02C ,,,OR
O RO
where R ; H, O R~ R2 H3C~~ H NO' 50 RO
R~ NOR2 . ,., ,~,OR O R~ Rz whexe R = H, II '/
O RO ~~'~NO' '~ O ICI O
H3C~~ H 51 H3C CH ~~~~~R~
3 Ri NO
ON~u~0Y~0 _ O ,.OR
O RO where R - H' O Ri R2 52 \'%~NO' HsC~~ H O O O

R
n~ / / R1 NO 2 Na02C~~~'OH
R~ NO

R~ O O O ~ rw( ) NaO~C'w'OH
O ,."
O R~~O H
z 10 CH3 (54) Iu (50), (51), (52), (53) and (54), Rl and RZ are selected from the group consisting of Cl-C~ alkyl and C6 Czo aiyl and substituted derivatives thereof e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated andlor phosphorylated.
The antihypercholesterolemic/autzhyperlipoproteinemic gemfibrozil has the formula:
O~~w~CO2H

C-Nitroso compounds of the invention herein derived from gemfibrozil include, for example:
0 0 ~ O~CCO2H ' (55) R~ NO I r Ri R2 ° ° O/~'J~ (56) oN'~
0 ~' Chi3 O%~~~~~C02H

° ° ° (57) 0'~~,.~COzH
HaC . \ . (58) O 0 R~ Rz w~~NO
O

0 0~~~~ NO
H3C ~~ /~\
O R~ Rz. . (59) CHI

0 0~,.~'~'~ R2 '~ CH3 In (55), (56), (57), (58), (59) and (60), Ri and RZ are selected from the group (60) consisting of C1-C6 alkyl and C6 CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.

The antihypercholesterolemic/antihyperfipoproteinemic clofibrate has the formula:
O"C02Et w CI
C-Nitroso compounds of the invention herein derived fiom clofibrate include, for example:

(61) c1 \~ 0Ii R~'/R2 O
O~~ ~"~NO
IoI o (62) W
ci rn (61 and (62), Rl and Rz are selected from the group consisting of Ci C6 all~yl and C6 Czo aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.

The calcium channel blocker nifedipiue has the formula:
j-~3C N CH3.
.
MeOZC ~C02Me NOz C-Nitroso compounds derived from nifedipine include, for example:
H

where , R = Me, R1, R2 (63) OZC C02R \\~~NO

~~~~ R2 R~ NO . .

R1 .
ON
1 O . where R is as in (63) . (64) NOR
O R

O where R is as in. (63) (b5) H3C~N~.CH3 In (63), (64) and (65), Rl and RZ are selected from the group consisting of C1-C6 alkyl and C6 CZO aryl and substituted derivatives thereof e.g., substituted with amino, hydroxyl and/or carboxy and/or Wlii.ch are sulfated and/or phospholylated.
The calcium channel blocker amlodipine has the formula:
N ~.NHz Me C-Nitroso compounds of the invention herein derived from amlodipine include, for example:
H

where R = Me, ~ Ri R2 ~'' I~NO
O o (66) R
\~~~~ z ,N O O~~
I 0'~ NH~..%~~~ R
z Rt NO
~C02Me ci NH O Ri R2 . . \~~~NO
Me O (68) ON ~O (69) ~NH2 Me NO

~O

(70) M
In (66), (67), (68), (69) and (70), Rl and RZ are selected from the group consisting of Ci C6 alkyl and C6 CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.

The calcium channel blocker.diltiazem has the formula:
C-Nltroso compounds of the. invention herein derived from dlltlazeln Include, for example:
(71) ~N
NO
O~ R

(72) ~N
~O

R~~
'NO
. . R2 (73) ~..~~~ N~
O
I O R~.R2 ~Nw (74) ~I
N
~N~
(75) ~N~

O
.~ S (76) N
U
~N~
In. (71), (72), (73), (74), (75) and (76), RI and RZ are selected fiom the group consisting of Ci C6 alkyl and C6-CZO aryl and substit-oted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboy and/or which are sulfated and/or phosphoiylated.
The calcium channel blocker verapamil has the formula:
hlC~ ~N w s '~ ..
~1;,C0~ . OCH3 OCH
C-Nitroso compounds of the invention herein. derived from verapamil include, for example:
NC
N
RO ~ l w V ( i OR OR (77) OR
where R ° CH3, O R~ RZ O O' ~~~J~NO , R
O
R~ NO

(78) OR
where R is the same as for (77) (79) . . (80) ~ OCH3 ocw3 NO
. . O R1 Nc ~ (81) N
RO \ ~ OR
OP, OR
where R is the same as in (77) Tn (77), (78), (79), (80) and (81), Ri and R2 are selected from the group consisting of Cl-C& alkyl and C6 CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy andlor which are sulfated and/or phosphoiylated.
The antacid cimetidine has the formula:
H

~S~N
N N
H H
C-Nitxoso compounds of the invention herein. dei~ved from cime'tidine include, for example:
O O .

NCN H3C N R1 ~ (8~) ~S~N
N N
N H

r~~NO
NCN H30 1 ~ O (83) \N~PI~S~
1~ H
In (82 and (83), Rl and R2 are selected fiom the group consisting of C1-C~
alkyl and C6-CZo aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated andlor phosphoiylated.
The antacid ranitidine has the formula:
H H
iN N~ O i y ,S 1 / a N

C-Nitroso compounds ofthe invention herein derived fromranitidine include, for example:
O
N N~i.~'S \ ~ N O (84) ~NOz R~

rN NHS ~OI Ni ~N02 O
NO
0 R~
O (85) R~
Iu (84) and (85), R1 and R2 are selected from the group consisting of Ci C6 alkyl and C6 CZO aril and substituted derivatives thereof, e.g., substituted with amino;
hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The bronchodilator albuterol has the.formula:
HO
H
OH
OH
C-Nitroso compounds of the invention.~herein derived from albuterol include, for example:
R0. ~'~
H
oR (s6) OR
O R1 R2 .
R= H, '~'~NO , O
~cvhere O O
. ~~~~~~ R2 R~ NO

_47_ R~ iV0 HO
.H Rz O (87) off OH
HO O
H ~~ ~~ NO
O R~ Rz (88) OH
OH
In (86), (87) and (88), R1 and RZ are selected fiova the group consisting of C1-C6 alkyl and C6 CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboy and/or which are sulfated andlor pliosphorylated.
The bronchodilator ipratropium bromide has the formula:
Bra C-Nitroso compounds of the invention herein derived from ipratropium bromide include, for example:
P,~ ~lo O R2 (89) off gr0 V o Ph O
~too ~ ) (90 OH Br0 Ph ~l (91) O O
O . R2 R~ NO
(92) Sr In (89), (90), (91), and (92), Rl and RZ are selected from the group consisting of Cl-C6 alkyl and C6-Cza aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/ox which are sulfated and/or phosphorylated.
The NMDA antagonist/skeletal muscle relaxant memantine has the formula:
HzN CNs C-Nitroso compounds of the invention herein de~xved from memantine include, for example:
R~ NO ( R2 ~ H ~CHg O (94) ON /C~N CH3 R~ ,R2'p~ H CH3 H2N ~X~~-~~i~Rz (95) ~H . R, No where X = O. NH
0 R~~~o N
Hz ~ 0 v~bere ~ is as iu (9S) (97) Where X is as in (95) In (93), (94), (95), (96) and (97), Rl and R2 are selected from the group consisting of Cl-C6 alkyl and C6 CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or Which axe sulfated and/or phosphoiylated.
C-Nitroso derivatives of antiproliferative agents are especially useful, as the NO group has antiproliferative egect and increases that of the agent before NO
derivatization.
The antiproliferative/tubulin binding agent 10=deacetylbaccatin llI has the formula:
HO - O OH
...
HO"" . 0 HO 0 z OAc C-Nitroso compounds of the invention lierein that are dercvatives of 10-deacetyl-baccatin III include, for example:
Ac0 O OH
0 (98) ", ON ~~~
Ol"' , 0 O HO O z OAc AcO O OH
ON R~
R2 O~a~ "''t O (99) O O . . ;H . , HO OBz OAc In (98) and (99), Rl and RZ are selected from the group consisting of Cl-C6 alkyl and C6 C2o aryl and substituted dei~atives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphoiylated.
The antiproliFerative/tubulin binding agent taxol h-as the formula:
Ago 0 off Ph O
~ ~ llJi77 Ph~'H~O"" ' H _ 0 OH HO OBz OAc C-Nitroso compounds of the invention herein derived from taxol include, for example:
AcO O OH
R~ NO ph 0 R2 ~~O",~ "'J~ ~ (100) ~O
0 , O OH HO ~ z OAc Ac0 O OH
O Ph 0 ~ (101) ON /~ ! ~' N ~Oa" O
R~ R2 O H pH HO 08z OAc In (100) and (101), R1 and R2 are selected from the group consisting of CI-C6 alkyl and C6 C2o aryl and substituted derivatives thereof; e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The antitubercular PA-824 has the formula:
OzN .
N O ' O
C-Nitroso compounds of the invention herein derived from FA-824 include, for example:

N
O
i X 'J~~;~ R2 ( 102) O ~ I - R~ N
X = O, NH

N O 0 R\ R2 X~~'~NO , O w ~ O (103) ~ = 0, NH
Iu (102) and (103), Rl and Rz are selected from the group consisting of Cl-C6 alkyl and Cs-Cao ~'Yl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphoxylated.

The CETP inhibitor JTT-705 (Okamoto et al., Nat~.re 406, 203 (2000)) has the fomnula: ' .
O
O .~ I g ~' C-Nitroso compounds of the invention herein derived from JT'T-705 include, for example:
O
NO , I S ~ ~' (104) z .
~~/~H
O
R
z NO
O' O
r O O .~ S (105) N ~
H
O
o , s W l (106) one R~

NO

O O i I ,S
(107) ~N
H

R~ R2 O i S \~~~~NO
I . R-_ O
0 O (108) R
R
R~ NO
Tn (104), (105), (106), (107) and (108), Rl and Rz are selected from the group consisting of Ct-C6 alliyl and C6-Czo aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or Which are sulfated and/or phosphorylated.
C-Nitroso compounds derived from SOD W imetics include, for example:
R~s R (109) R~~R Where R is H, C1-C6 alkyl, C -C a s ao O
O ~ O
R~ R2 R or ' 2 ~~' I~NO
O

R ' ' R
.H . ~ {110) M-L~
H
R I -N .~ R
where M is, for example, manganese, iron or cobalt, L is halide, n ranges from 0 to 4 depending on the valence of M, and R is as in ( 109).
In (109) and (110), Ri and RZ are selected from the group consisting of Cl-C6 all~yl and C6-CZO aryl and substituted derivatives thereof e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The xanthine oxidase inhibitor alloptu5nol has the formula:
~~~~1 w. l , ~
C-Nitroso compounds dea~ved from allopurinol include, for example:
~ ,w ~O (111) Ot '(~V
R~'~ O
~z O
~l ~'V ~ ~ , N
O
O ~ ~ (112) 01~ R2 ~T

ON R~ <.
Q
~N O (113) UH
~o O r ~1,N o ( 114) OH
Tn ( 111), ( 112), ( 113) and ( 114), R1 and R2 are selected from the group consisting of Cl-C6 alkyl and C6-CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The COX-2 inhibitor Celebrex has the formula:
t~
HEN'' ~~3 Hs C-Nitroso compounds derived from Celebrex include, for example:
(115) H~N~S ~ I
N v CFa R~ ~~
~12~1~~ -~ I (116) -N
N
Rj NOI
Rz C~ O
(117) a, ,a H~N~S ~' ~ . (11~) N Pd O
v I \ w R' r //~
~-iaC ~ NC7 R~

_58_ In ( 115), ( 116), ( 117) and ( 118), Rl and RZ are selected from the gxoup consisting of Ci C6 alkyl and C6-CZO aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The COX-2 inhibitor indoinethacin has the formula:
c02H
C-Nitroso compounds derived from indomethaciu~ include, for example:
(119) COzH
OcH3 'cO~H (120) ~~3 R ~

(121) In ( 119), ( 120) and ( 121), R1 and RZ are selected from the group consisting of C1-G6 allcyl and C6 C2o aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The COX-2 inhibitor L-745,337 has the formula:
~~~OzCH~
i ~f i~
F F
O.
L-7~.5,33'l C-Nitroso compounds derived from L-745,337 includ.e;.'fot' example:
(122) F
i1H~420H~
O (123) F ~

NQ O

NHSOaCH3 S
( 124) R
O
In (122), (123) and (124):
RT R.z R=
~~~ R2 , ~ i~c~
Ri ~p o and R1 and RZ are selected from the group consisting of Cr-C6 alkyl, C6 CZO
aryl and substituted derivatives thereof e.g., amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
The COX-2 inhibitor etudolac has the formula:
~ tJ~H
N
~ v C-Nitroso coanpounds derived fio~i~etudolaa iuchide,,;for example:
R~ O CO~H
ONE N . (125) N w O~l R~ o Co2~
o ~ ~ (126) Rz -' .
NQ
R R~o ~~2t~ (127) z ~i Rz (128) In ( 125), ( 126), ( 127) and ( 128), Rl and R2 are selected from the group consisting of CnCs all~Yl, C~-Czo aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy and/or which are sulfated and/or phosphorylated.
In all cases where Rl, R2, R3, R4 or RS are defined above where H is not one of the named groups, Rl, Rz, R3, R4 and RS can also be H, provided that the NO is attached to a tertiary carbon, i.e., so that defining Rl, R2, Rg, R4 and/or RS as H does not make NO attached to a carbon which is not a tertiary carbon.

Additional C-nitroso compounds herein derived from the antianginal nadolol include:
O. I ~ (300) HO OH
O

HsC~ NO
H3C NO O~ ~ , 301 Me02C I \ OH ( ) HO
O~
HO off H (302) ON
FaC~ CF3 (303) NC NO O
Me02C I \ OH
HO

Additional C-nitroso compounds herein derived fiom the antihypertensive pindalol include:
~O
(304) H
N (305) O NO
HsC CF3 'OH
\/NH
(306) (307) -OH
~NH
Additional C-nitroso compounds herein derived from the ACE inhibitor enalapi7l include:
.~ H02C,, Et02C
N N NO (308) H O O CHs Ef02C HOZC, N~-NO (309) Et02C H02C'/~'~
N , N~NO (310) H O '~ 'COzMe Additional C-nitroso compounds herein derived from the bronchodilator ipratropium bromide include:
H ~ Bra (311) h O
~N
OH gr~ (312) Me02C
NO O Ph O

O+
~N
(313) HsC OH Br0 O Ph O NO
O
Additional C-nitroso compounds herein derived from the CETP inliibitor JTT-70S
include:
O
O , S
_ ~ ~ ~ (314) NC H
ON
O
S (315) O
N ~
FsC H
ON

O
O ~ ~ S ~ (316) ~N
Me02C H
ON
C-nitroso compounds herein which are acyclic compounds include:

(317) F3C C~OH

ON " ~OH (318) Et02C OH

O
NO (319) FaC OH

NC NO
NC> C02H (320) The compounds (1) - (128) and (300 - (320) axe meant to be exemplary and as one skilled in the art would understand, in many cases the chain on which the NO
is substituted can also be in a different location from the one depicted.
In many of the exemplified compounds, the nitric oxide bearing fragment is linked through an ether or amino linkage. The ether linkage has the advantage of stability z~ vivo.
Alternatively, in. some instances it can be advantageous to link the NO-bearing fragment through an ester linkage.
Examples of C-nitroso compounds of the invention herein where NO-bearing fragment is linked through an ester linkage are set forth. below:
(129) o~?~~o Q ~9 r co~ Ra NOD (130) p R~
-, ~~ H
~ ~~o R,j (131) ~~2 O
I ~H
...- ~ O (132) W I r O
In (129), (130), (131) and (132), Rl and RZ are selected from the .group consisting of Cl-C6 alkyl and C6 C2o aryl and substituted derivatives thereof, e.g., substituted with amino, hydroxyl and/or carboxy audlor which are sulfated and/or phosphorylated, or can be H, provided that defining Rl and RZ as H does not make NO attached to a carbon which is not a tertiary carbon. The compounds (129), (130), (131) and (132) are meant to be exemplary, and knowing the above, one skilled in the art, could conceive of many other C-nitroso compounds of the invention herein Where NO-bearing fragment is linked through an ester linkage.
An example of a Compound (129) is:
G02t-1 (129a) p NO
i D
.Au example of a Compound (130) is:
~ CO~H O ' (130a) 3~C~
t3 O Q

Both the compounds (129a) and (130a) are obtained by nitrosylation of a carbon atom having a pKa less than about 10. .
We tm~ now to the synthesis of the C-nitroso compounds of the first embodiment herein.
Several methods applicable to synthesizing C-nitroso compounds are disclosed in Boyer, J. H., 'methods of Formation of the Nitroso Group and its Reactions" in The Chemistry ofthe Nitro and Nitroso Groups, Part I, Feuer, H., Editor, John Whey & Sons, New York (I969) at pages ZI5-299 and in Touster, O. in Oxganic Reactions, Vol.
7, John Wiley & Sons, New York (1955) at pages 327-377 which are incorporated herein by reference.
In a method which is applicable to nitrosylation of carbon acids with pKa's less than about 15, the carbon acids can be directly nitrosylated with sodium nit~xte and an acid such as glacial acetic acid after the method of Sklyar, Yu. E., et al., Khimiya Geterotsikli.cheskil~h Soedinenii, 5, 70-73 (1969). This method is useful fox preparing the subgenus of compounds herein which are obtained by nitrosylation of a carbon acid having a pKa less than about 10.
In a method which is applicable to nitrosylatiug carbon acids with pKa's between about 15 and 30, nitrosylation is carrited out by formation ofthe enolate and trapping the enolate by a nitrosonium equivalent. The enolate can be trapped directly or isolated as the silyl enol ether or au equivalent. This method is useful for preparing the subgenus of compounds herein obtained by nitrosylation of a carbon acid having a pKa ranging from about 15 to about 20. It is the method used in Example I hereinafter for preparing dimeric 2-[4'-(a-nitroso)isobutyrylphenyl]propionic acid.
In a method useful for synthesizing C-nitroso compounds regardless of the acidity, the carbon acid is converted to the co~Tasponding hydroxyl amine which is oxidized, for example, using silver carbonate on Celite.

_71_ In the case of unstable C-nitroso compounds, it can be desirable to introduce or unmask the C-nitroso fiagment only in the final step of the synthesis, or at least as Iate in the synthesis as possible. In one such xoute, the synthesis ofthe C-nitroso drug will first incorporate au appropriate fragment and nitrosylation is carried out only after synthesis is i' complete. An example of this route is set forth below:
tb sse, RjX ~ ~ O 1) HBr, 6rz i ii)HO~°H '~~ ii) FP?'S . ~'t ~ I ~ PYr OH
IIl) H~, H~J
1V~I~IO~ HOqc %O2'!
(133) In the above reaction cheme, R1 can be selected.fi:o~n the.,group...can5isting:ofC1-C6 alkyl and C6-CZO aryl and substituted derivatives thereof (as defined for Rl and R2 above), and X is chlorine or bromine and PPTS is pyridiniumparatoluene sulfonic acid anal '~yr"
is p~n~idine.
This route is especially suitable for the preparation of compounds derived from parent carbon acids with especially low pKa values, typically less than 15 and preferably less than 10. For compounds derived from parent carbon acids with higher pKa values, it is preferable to carry the C-nitroso moiety masked as the bis-protected hydroxylamine; the C-nitroso functionality is unmasked, for example, late in the synthesis, following attachment to a conventional drug, by mild oxidation with, for example, silver carbonate on Celite; an example of this mode of synthesis is set forth below:

_72-G i) I.DA, the (CHBy~iC! O I
~ ~ !l) TiClq, isoqmyin(trife ) PG O I
'(" 'COyTMSE ~, ~CO~ ii)ii) 8= I
Ili) Zn, HOAc NHOH
(MOKPG~
PG0~0 '' PGay~.~o ncc o ---s~.. . I) neprntect O
PGO O (PG2)(NO)~p ii A O ~' ~ ~~
O _ H ~ ) 9 3 t;xlfte N\~9 ' cH3 ' ~ Ic1 . H c (134) r r .~ H3 HO H ' Hue,., HOC'' ~ r In this reaction, LDA means lithium diisopropyl amide, . .TMSE means trimethylsilylethyl, R is TMSE, PG is a protecting group, and DCC is ~dicyclohexylcarbodiimide.
Derivatized compounds can be prepared utilizing as nitrosylating agent a bromomethylketone derivative of either 3-nitroso-2,4-pentane dione or 4-nitroso-2,3-butadione.
Substituted 3-nitroso-2,4-pentadiones can be prepared by the following reaction scheme:
i) base, RiX O
O i) Hz; Pd/C O 0 HO,~OH
--~-.~ '~ --_._.
ii) NaNOz; HOAc ii) PG ~/~ PG 1 eq; pPTS
i) base, R2X
ii) Ease, RzX %~0 I) HzO~.pPTS O 0 ii) Brz, Ht3r R NHOPG iii) base, R~X ----------~ Ra Br R3 RzRi NHOPG iii) AgC03; Celite R R NO

In. the above reaction, scheme "PG" stands for protecting group and 'OPTS"
stands for pyridinium paratoluene sulfonic acid, Rl, R2, R3 and R4 are the same or different and can be the same as Rl is defined for reaction schemes above, and X is chlox~ne or bromine. The preparation is briefly described as follows: A group is introduced by nucleophilic substitution at the most acidic position in standard fashion. Intxoduction of this group prevents formation of the oxime following nitrosylation. The precise identity of the group is.chosen to control the reactivity of the C-nitroso derivative. Electrophilic nitrosylation with nitrosonium is followed by reduction to the hydroxylamine and protection as the bisacyl derivative, as described in 'Bis-protected hyds~oxylamin.es as reagents in organic synthesis. A review:"
in Romine, J. L., Org. Prep. Proced. Int. 28, 249-288 (1996). Differentiation ofthe drone by monoprotection as the ketal is followed by introduction of one, two or three groups by nucleophilic substitution in the standard way. Deprotection of the ketal and the hydr oxyl amine is followed by mild oxidation to the C-nitroso compound with, for example, silver (1) salts immobilized on Celite. Finally, conversion to the bromomethyl ketone with bromine and hydrobromic acid provides the derivatizing agent.
Substituted 4-nitroso-2,3-butadiones can be prepared according to the following reaction scheme:
OOH /~ ij base, R~X r J ~ R ii pGPd/C
HO O O ii) base, RzX O ORi 7 e~ ~ iii) LDA then H3)3g,Gl ~~NO iii) NZO, pPTS ~
O iv) TiCl4, isoamylnitrite 0 O I) Deprotection O
Ri R2 ii) AgC03 Rp Rz .----~ Br ~NHOPG iii) grz, NBr \~~NO
.f0 O
In the above reaction scheme, 'OPTS" is pyridimium paratoluene sulfonic acid, '2,DA" is lithium diisopropyl amide and "PG" means protecting group Rl and R2 can be the same or different and can be the same as for the reaction schemes set forth above, and X is chlorine or bromine. The preparation is briefly described as follows: The drone of 2,3-butadione is differentiated as the monoketal and is then substituted by nucleophilic substitution in the standard fashion. Nitrosylation through the silyl enol ether, followed by protection of the C-nitroso group as the diacylated hydroxylamine precedes deprotection ofthe ketal, regeneration of the C-nitroso functionality and bromination to the reactive a-bromoketone.
Iu the synthesis of compounds of the first embodiment herein, the carbon acid pKa of the starting material can be adjusted down by the provision therein of an,electron withdrawing atom or group and the carbon acid pKa can be adjusted up by the provision therein of an electron releasing group.
For example, an acidic center can be introduced, e.g., formation of a ketone group from the carbon adjacent the carbon to be nitrosylated to increase the acidity and provide lower carbon acid pKa starting material. This approach was used in the synthesis of dimeric 2-[4'-(a-nitroso)isobutytylphenyl]propionic acid fiom ibuprofen set forth in Example I below.
In the synthesis of Example r, ibuprofen (carbon acid pica of approximately 50 - 55) was converted to 2-(4'-isobutyrylphenyl)propionic acid (carbon acid pKa of about 20) by this approach and the latter was converted to the final product by the method of nitrosylating carbon acids with pKa's between about 15 and 30 described above. The reaction scheme used in Example I to convert ibuprofen to dimeric 2-[4'-(a-nitroso)isobutyrylphenyl]propionic acid is set forth below where 1A is ibuprofen, 4A is 2-(4'-isobutyrylphenyl)propionic acid and 6A is the dimeric product.
i) TMSCI, EtOH
ii) CrU3, AcoN; ~ Co H i) TMSCI, Et3N
COzFi $0_55 C ( ~ ii) Isoamylnitrite, TiCld --y- i , iii) 15% aq Na01-UMeOH
1A , 4A
-Fi0 C / \ 0 .-~ y O_ ANN~
_p \ /

Tn. the above reaction scheme, "TMSC1" stands far chlorotrimethylsilane.

In summary, there are fundamentally at least two different ways of making compounds herein. One of these is to modify the parent drug to introduce of the first embodiment herein functionality (ketone or drone) that allows C=nitrosylation. It is by this method that the nitrosoketoibuprofen is made herein. The other ofthese is to attach a piece or fragment to the drug that allows formation of -CNO. One method of carrying out the latter is via a bromoketone to link via ether, amine or ester. Instead of using a bromoketone, a carboxylic acid derivative can be reacted with hydroxy group or amine group of a conventional drug to obtain an amide or ester linkage.
The Compound (129x) can be prepared by the following route of synthesis:
~~ 6r"C02Ei: , Zn-Cu O .. , o=ar= 0 COzH '~
ii) cnnc. HCI
CO H ~) CCI~CHZOH, H~ ~ C02H ~ r) MSCl, pyr i1) ~, CH~S02C1, pyr 0 ti) ~CICl4, isflarriyl nitrite 129a OH iii) Zn, HOAc 0 ( ) O
The Compmuaid (130a) can be prepared by the following route~of synthesis:
O~O O
HOC
NaOH
r) CChCH20H, H+
C02H ii) ~~ CH3SO2Cl, PYr -'"' (1~0a) OH !i7 Vin, HOAc iv) NaN02, HOr~c We turn now to utility of the C-nitroso compounds of the first embodiment herein.
The C-nitroso compounds of the first embodiment herein have utility as NO
donors and in such function provide relaxation and platelet inhibiting effect. Thus, C-nitroso compounds of the first embodiment herein are useful to prevent restenosis following angioplasty in patients at risk for restenosis following angioplasty and to inhibit platelets to prevent coagulation and to treat angina in patients at risk for coagulation and thrombus formation. The NO donor function also provides the following therapeutic effects: inhibition of microbes and treatment of impotence, asthma, heart failure, stroke, arthritis, ARDS, cancer and any pathological proliferation of cells and any NMDA related injury.
As indicated above, the C-nitroso compounds of the first embodiment herein with high NO-donating capacity (from carbon acids with pKa's less than about 10) exhibit weak (micromolar concentration) effects, probably through nitrite and are potentiated by added glutathione or similar low molecular weight thiols. These compounds cause formation of nitrosoglutathione and are therefore especially usefixl to treat patients in need of nitrosoglutathione, e.g., patients with cystic fibrosis, asthma, hypoxia and ischemic disorders.
As indicated above, the C-nitroso compounds of the first embodiment herein with weak NO-donating capabilities (fiom carbon acids witli pKa's ranging fiom about 15 to,,about 20) show high activities through specific nitrosylation of strongly nucleophilic targets and are therefore useful to nitrosylate thiols in proteins in highly nucleophilic milieus and thus are usefixl to treat patients in need of nitrosylated proteins, e.g., patients with hypertension, neurodegeneration and painful crisis of siclde cell disease.
When C-nitroso compounds ofthe fast embodiment herein are derived fiom nonsteroidal anti-inflammatory drugs that iilhibit COX-1 as well as COX-2, the C-nitroso compounds are usefizl to treat inflammatory or painful disorders including artluitis, coronary artery disease and urinary incontinence and improve the profile of selective inhibitors of COX-2, e.g., in the treatment of angina. The nitrosoketoibuprofen prepared herein has these utilities.
As indicated above and will be discussed in more depth in the description of advantages below, the stability of the dimeric form of isolated C-nitroso compounds of the first embodiment herein improves compound lifetime and provides modulated bioactivity.
This characteristic permits their use as sustained release drugs. Such stability also connotes utility as prodrugs. Because spontaneous release of NO is both controllable and small, many C-nitroso compounds will be active only in the presence of small molecule activators, e.g., low-molecular weight thiols acting as carrier s of NO (in an appropriate redox form) from the C-nitroso compound to a biological target.
We turn now to dosages and methods of administration for the C-nitroso compounds ofthe first embodiment herein when they are used for therapeutic utility.
In general, dosages range from l ,ug/lcg to 1,000 mg/kg and vary depending on the specific C-nitroso compound. Dosages for specific compounds are readily established by standard dosage establishing procedures. The normal dose of the parent chwg can be preserved by only using part of it as the C-nitroso derivative. The reason for the wide range is that many compounds are embraced by the invention.
Routes of administration include, for example, oral, parenteral including intravenous, inhaled, nebulized, and topical.
When the C-nitroso compound of the first embodiment herein is derived from a conventional drug, the dosages utilized are those in use for the conventional chug and the methods of use are those for the conventional dmg but, as indicated above, only part of the drug is administered as the C-nitroso compound with the rest being administered as the conventional dz-ug, if necessary.
When the C-nitroso compound is one obtained by nitrosylation of a carbon acid having a pKa less than about 10, it is preferably administered in a concentration ranging from 1 nanomolar to 100 micromolar as an aqueous solution unless potentiation is provided by glutathione or other low-molecular weight thiol whereupon the C-nitroso compound is preferably administered in a concentration ranging from 1 to 900 nanomolar and the glutathione is administered in a concentration ranging from 1 micromolar to 100 millimolar.
When the C-nitroso compound is one that is obtained from a carbon acid having a pKa ranging from about 15 to about 25, e.g., about 15 to about 20, the C-nitroso compound is preferably administered u2 a concentration ranging from about 1 nanomolar to micromolar.
We turn now to the ibuprofen derivative, i.e., dimenc 2-[4'-(a-nitroso)isobutyylphenyl]propionic acid. It is preferably administered as a pill, tablet or capsule or the like, with only part of the ibuprofen being administered as the C-nitroso derivative, e.g., one part by weight ibuprofen derivative, to 1,000 parts by weight uuderivatized ibuprofen to provide 400 mg on an ibuprofen basis, three to four times day and from I nanomolar to 100 micromolar C-nitroso compound concentration.
The compounds of the first embodiment herein are advantageous over the C-nitroso compounds known heretofore in activity and/or in solubility.
We turn now to the advantages ofthe C-nitroso compounds ofthe first embodiment herein over O-nitroso compounds and S-nitroso compounds as NO donors.
A major baiTier to use of organic nitrites and nitrosotliiols as NO (or nitrosonium) donors is their instability. For example, nitrosothiols undergo rapid decomposition to yield inter alia nitric oxide radical and a sulfi2r radical. In contrast, C-nitroso compounds ofthe first embodiment undergo a dimerization reaction to produce a solid, stable dimer. As indicated above, this dimerization reaction proceeds spontaneously during isolation of C-nitroso compounds and the dimexization is greatly favored for a-acyl C-nitroso compounds.
In general, the dimers are solid and stable, capable ofbeing stored at ambient teruperature in the presence of oxygen and light for months. The C-nitroso compounds herein have a significant advantage over O-nitroso and S-nitroso compounds ofthe fast embodiment from the standpoint of shelf stability.
The C-nitroso compounds ofthe first embodiment herein are also advantageous over O-nitroso and S-iritroso compounds as NO donors in that their functionality, i.e., NO donating potential and reactivity, can be tailored, while this is not the case fox O-nitroso and S-nitroso compounds.
We turn firstly to tailoring the NO donating potential of C-nitroso compound ofthe first embodiment herein. This can be done in three ways. Firstly, the rate of transfer of nitrosonium equivalent is directly proportional to acidity. Thus, NO donating potential is increased by obtaining C-nitroso compound from starting material with lower pKa. Secondly, the NO donating potential is related to the position (equilibrium constant) ofthe dimer-monomer equilibrium ythermodynamics). This property is because, as indicated above, the dimer is stable and inactive whereas the monomer is active. Thirdly, the NO
donating potential is influenced by the rate of interconversion of the dimer and monomer (kinetics).
This feature can be utilized, for example, by positioning an aryl alpha to the nitroso carbon to slow down the rate of interconversion to monomer. On tla.e other hand, the NO-donating capability of organic niriites and niti~osothiols is largely a function of the heteroatom (oxygen or sulfur); there is little in the way of relationship between structure and activity.
We tiun now to tailoring of the reactivity of C-nitroso compounds. This can be accomplished sterically or electronically. We tum now to the steric tailoring of reactivity.
The addition of steric bulk at the a-carbon slows transfer of a nitrosonium equivalent. Thus, for example, highly hindered protein sulpliydiyl receptors can be protected against S-nitrosylation through use of highly hindered C-nitroso donors. We tum now to electronic tailoring ofreactivity. Firstly, the rate oftransfer ofnitrosonium equivalent is directly proportional to the acidity of the parent carbon acid. Secondly, the reactivity can be tailored by selecting starting material with groups that can tailor donating potential.
For example, addition of groups such as acyl and electronegative substituents, will lower the acidity of the carbon acid and in turn enhance the NO''~ donating capacity of the C-nitroso compound.
Moreover, alteration of groups changes the form of nitric oxide liberated. The alteration of groups can change the acidity as much as 104°, greatly exceeding the range available with sulfur or oxygen-based conjugates.
Methods for providing different groups in C-nitroso compound are available in the methods of synthesis described above where bromometliylketone derivatives of either 3-nitroso-2,4-pentauedione on 4-nitroso-2,3-butadione axe used and these groups can influence the monomer-dimer properties and NO-donating potential of the final product.
As indicated above, the C-nitroso compounds ofthe first embodiment, when derived from conventional drugs, can be used in place of the conventional drug and the methods of use are those for the conventional d~.~ug, although dosage may be varied to provide therapeutically effective amount. Thus in one case, there is provided a method oftreating a patient with au inflammatory or painful disorder, comprising administering to said patient a therapeutically effective amount of a C-nitroso compound having a molecular weight ranging fiom 225 to 600 on a monomeric basis wherein a nitroso group is attached to a tertiary carbon which is obtained by nitrosylation of a nonsteroidal anti-inflammatory drug having a carbon acid pKa ranging fiom about 15 to about 25, e.g., about I5 to about 20, or a nonsteroidal anti-inflammatoiy drug modified to have a carbon acid pKa ranging fiom about 15 to about 25, e.g., about 15 to about 20. In another case, there is provided a method for treating a patient with a disorder which is treatable with an analgesic dt~ug comprising administering therapeutically effective amount of C-nitroso compound as described in the above sentence except that the treating agent is a nitrosylated analgesic drug having a carbon acid pKa ranging from about 15 to about 25, e.g., about 15 to about 20, or an analgesic drug which has been modified to have a carbon acid pKa ranging from about 15 to about 25, e.g., about 15 to 20, and then nitxosylated. In still another case, there is provided a method for treating a patient with angina comprising adaninistering C-nitroso compound as described in this paragraph except that the treating agent is a nitrosylated antianginal drug having a carbon and pKa ranging from about 15 to about 25, e.g., about 15 to about 20, or an antianginal chug modified to contain said carbon acid pKa and then nitrosylated. In still other cases, autihypextensive drugs, diuretic chugs, ACE inhibitions, antihypercholesterolemic/antilipoproteiuemic drugs, calcium channel blockers, antacids, bronchodilators, NNIDA
antiagonist/skeletal muscle relaxant chugs, antiproliferation/tubuliu binding agents, antitubercular agents, CETP inhibitors, SOD mimetics or xanthine oxidase inhibitors which have carbon acid pKa ranging from about 15 to about 25, e.g., bout 15 to about 20 are nitrosylated or axe modified to contain carbon acid pKa less than 25 and then nitrosylated to provide compound of the first embodiment herein and administered in therapeutically effective amount to patient for which the dt~ug is indicated.
Moreover, C-nitroso compounds of the first embodiment herein and other C-nitroso compounds derived from carbon acids with pKa values less than about 25 can be incorporated into polymers fox coatings on medical devices. In the case of such coatings, polymerizable C-nitroso compounds can be copolymerized with appropriate monomers to yield plastics ox elastomers as desired.
The polymers into which C-nitroso compounds of the first embodiment herein and other C-nitroso compounds with pKa values less tlian about 25 can be incorporated include all biocompatible polymers, including PVP and PVP-urethane copolymers; hydrogels;
polylactides and polylactide-co-polyethyleneglycol; polyacrylonitriles, polyacrylonitrile/polyacrylamide/polyacrylic acid copolymers; polyurethanes, polycarbonates, polyethexs and copolymers of the three; silicone polymers axed copolymers;
carbohydrate polymers, including starches and modified starches, cellulose and cellulosidic materials, chitin and chitosan, glycosamine glycans, including hyaluronic acid, chondroitin and chondroitin sulfate, wherein the polymer has been modified to incorporate C-nitroso moieties derived from carbon acids with pKa values less than about 25. The C-nitroso moieties can be bound as esters or ethers to pendant hydroxyl groups, as esters to pendant carboxylic acids or as amines or amides to pendant amino moieties. The nitrosylated polymer itself can be prepared in a variety ofways. Nitrosylated monomers can be incorporated into a growing polymer du~.zng either a free radical, ionic, metathesis or living polymerization.
Alternatively, a completed polymer can be dei7ivatized following synthesis to incorporate the above listed residues by treating, for example, hydroxylated or amine-containing polymers with carboxylic acid chlorides or alkyl halides, carboxylate-containing polymers with alkyl halides. Finally, a C-nitroso precursor, for example, a monomer containing a drone or a vinyl silane can be polymerized into a growing polymer chain by a free radical, ionic, metathesis or living polymerization and then nitrosylated following polymerization by exposure to a source of nitrosonium, for example acidified nitute, titanium tetrachloride and an alkyl nitrite, respectively.
Said polymers, can have weight average molecular weights (determined by light scattering) xanging, for example, from 50,000 to 500,000.
As indicated above, one embodiment herein is directed to polymers incorporating C-nitroso moiety derived from a carbon acid with a pKa less than 25, having a weight average molecular weight (as determined by light scattering) ranging from 50,000 to 500,000. The term "C-nitroso moiety" means that some portion of the polymer includes C-nitroso derived from a carbon acid with a pKa less than 25. This kind of polymer is described above and includes, for example, a hydroxylated, amine-containing or carboxylate-containing polymer incorporating a C-nitroso moiety derived from a caxbon acid with a pI~,a value less than about 25, e.g., a liydroxylated or amine-containing polymer derivatized with a carboxy?uc acid chloride or alkyl halide containing a C-nitroso moiety derived from a carbon and with a pKa value less than about 25 or a carboxylate-containing polymer derivatized with an alkyl halide containing a c-nitroso moiety derived from a carbon acid with a pKa value less than about 25.
As indicated above, another embodiment lierein is directed to a medical device having a therapeutically effective coating of C-nitroso moiety incorporating polymer as described in the above paragraph. This embodiment includes stents coated with C-nitroso moiety incorporating polymer as described above to prevent coagulation, a catheter coated with C-nitroso moiety incorporating polymer as described above to prevent infection and a drain coated with a C-nitroso moiety incorporating polymer as described above to prevent infection and coagulation.
We turn now to methods utilizing the polymers herein incorporating C-nitroso moiety.
These methods include, for example, a method for prophylaxis of a patient who is at risk for coagulation or thrombus formation or microbial or viral infection compzising contacting tissue in the area that is at risk with polymer herein incorporating a C-nitroso moiety, e.g., by inserting a stent coated with said polymer into a patient who has or is at zxsk for restenosis.
We tuna now to the C-nitroso compounds of the second embodiment herein. These contain the moiety -C-N(O)X-where X is S, O or NR where R is selected from the group consisting of C1-C6 alkyl which is unsubstituted or which is substituted with one or more alcohol, ether; ester or amide groups which contain from 2 to 10 carbon atoms; and has a molecular weight ranging, for example, from about 100 to about 1,000.
A prefeiTed subgenus of the second embodiment herein comprises the structure:

(135) where X is S, O or NR where R is as defined for the genus of the second embodiment and n ranges from 0 to 4 and the coiTesponding protonated compounds (instead of existing with the negative charge).

The structure (135) may be substituted with C1-C6 alkyl or Cl_~ alkyl carbonyl and includes the modification that the carbon pendant to X and a carbon within the parentheses can also be part of another ring. Fox example, a compound of the second embodiment herein.
1S:
O
(135a) The compounds ofthe second embodiment form spontaneously from coiTesponding C-nitroso compounds that contain alcohol, tliiol or amine. For example, the Compound (135a) is formed by:the following route of. synthesis:
;~ sLci, pyr ii) T~rlscl Iii) Ticl~., isoa y nit~sca ~H ~~ #~~Cp~, i~IeCJHIH~O
~t~ . O
. O _~.. ~ k N'' OH
where Bz stands for benzoyl.
The compounds of the second embodiment herein have utility as NO donors as described above in conjunction with the C-nitroso compounds of the first embodiment and are used with the dosage ranges and routes of administration desca.-ibed in conjunction with the C-nitroso compounds of the first embodiment and are characterized by similar stability to the dimers of the C-nitroso compounds of the first embodiment.
We turn now to the embodiment herein directed to inhibitors of COX-2 where a tertiary carbon on an oxygen or a sulfur is nitrosylated.

Examples of inhibitors of COX-2 where a tertiary carbon is nitxosylated are compounds (115) - (128) set forth above.
Examples of inhibitors of COX-2 where an oxygen or sulfur is nitrosylated include, for example, derivatives of Celebrex, indomethacin, L-745,337, and etudolac.
Examples of compounds derived from Celebrex include the following:
o, .o H~~~~ f (ZOO) oiVYx' ~( ~ ,o _s H2N ~ ~ ~ .. ~ (201 ) N ' -YNO
~a ~3~
Examples of compounds derived from indomethacin~include the following:
(202) ?C.~.YNO
R.~ Rz ~3 CO2H (203) .An example of a compound derived from L-745,337 is P~iHSO~GH3 .
S (204) w I I ' Ry R~
~;~~' YN O
\v Examples of compounds derived from etudolac include the following:
ONY~~
N. _ (205) ~o R~ / X ~ oaH
Ftx N
l (206) f Iu the compounds (200), (201), (202), (203), (204), (205) and (206), Y is S or O; R1 and RZ are H or Cl-C6 alkyl; and X is Cl-C~ alkyl, C6 Czo aryl and substituted derivatives thereof, e.g., substituted with amino, hyelioxyl, and/or carboxy and/or which are sulfated and/or phosplioiylated.
The COX-2 inhibitor compounds whicli are O-nitrosylated are obtained from the parent alcohol by treatment with au appropriate nitrosylating agent, e.g., acidified nitrite, nitrosyl chloride, nitrosyl bromide, nitrosonium perchlorate, nitrosonium hydrogen sulfate or nitrosonium tetrafluoroborate.
The COX-2 inhibitor compounds whicli are S-nitrosylated are obtained from the parent thiol by treatment with an appropriate nitrosating agent, e.g., those set forth in the paragraph directly above or alkyl nitrite.
The dosage on a COX-2 inhibitor basis is the same as the dosage for the underivatized COX-2 inhibitor. To effect this, only pact of the COX-2 inhibitor can be administered in the form of nitrosylated compound. The route of administration is the same as for the uuderivatized COX-2 inliibitor.
The invention is illustrated by the following working examples.
Example I
Synthesis of Dimenc 2-Lea-Nitroso isobut~-~phenyl]propionic Acid The synthesis of dimeric 2-[4'-(a-nitroso)isobutyrylphenyl]propionic acid was camped out according to the reaction scheme for this set forth above as follows:
To a solution of ibuprofen 1A (9.89g, 48 mmol) in anhydrous EtOH (35 mL) was added chlorotrimethylsilane (18.27 mL, 144 mmol) at room temperature, and the mixtiue was stiiTed at the same temperature for 2h. After the removal of the excess EtOH
and chlorotrimethylsilaue under reduced pressure, the oily residue was treated with ice-cold saturated NaHC03 (150 mL), and the resulting mixture was extracted with hexaues (450 mL).
The liexanes solution was washed with brine (3x50 mL), and ch~ed over anhycli~ous Na2S0z.
Evaporation ofthe solvent afforded ethyl 2-(4'-isobutylphenyl)propionate 2A
(11.24 g, in 100% yield) as a colorless oil.
Ester 2A (11.23 g, 48 mmol) was added dropwise to a stirred suspension of Cr03 (20.8 g, 208 mmol) in acetic acid (AcOH) (34 mL) and H20 (1.l mL) within 30 min, maintaining the reaction temperature at 45-55 °C. After the completion of addition, the _87_ mixture was stiiTed for 20 min, and then the mixture was lieated with stiix~ug at 50-55 ° C for additional 85 min, giving a blue-black suspension. The AcOH was removed under reduced pressure, and the residue solid was suspended in ice-cold H20 (400 mL), and e~.~tracted with EtOAc (450 mL,). The extract was waslied with bring (5x50 mL), and dried (NaZS04). The crude products were purified by flasli chromatography (eluting witli 7% EtOAc in hexanes) to give uureacted ester 2A (2.78 g), followed by ethyl 2-(4'-isobutyrylphenyl)propionate 3a (4.3 g, 48% yield based on consumed 2A) as a light-yellow oil.
Fifteen percent aqueous NaOH (10 mL) was added to a solution of 3A (3.2 g, 12.9 mmol) in MeOH (150 mL), and stilled at room temperature for 2 h. After the removal of the MeOH by evapor ator, the dark-brown residue was treated with ice-cold 2M HCl ( 100 mL), and the resulting grey-white suspension was extracted with EtOAc (400 mL), and finally ch~ied (Na2S04). Flash chromatographic purification of the crude products (eluting with 60°t° EtOAc in hexaues) afforded 2-(4'-isobutyrylphenyl)propionic acid 4a (2.5 g, 88%
yield) as an amorphous solid.
To a stored mixture of 4A {1.59 g, 7.2 mmol) and triethylamine (3.03 mL, 21.7 mmol) was added chlorotrimethylsilane (2.75 mL, 21.7 mmol) at room temperature, and then a solution of sodium iodide (3.26 g, 21.7 mmol) dissolved in anhydrous acetonitrile (25 mL)~
was introduced in one portion. The mixture was stilled at room temperature for 8 h, then extracted with hexanes {400 mL). The hexanes extract was washed with ice-cold brine (2x30 mL), and dried (Na2SOd). Concentration ofthe solvent afforded trimethylsilyl 2-[4'-(1-tri~uethylsiloxy-1-isobutenyl)phenyl]propionate 5A (2.08 g, 79% yield) as a viscous oil, which was used without filrther purification.
A solution of 5A (2.1 g, 5.7 mrnol) dissolved in anhydrous CH2Cl2 (25 mL) was cooled to -10°C. Isoamyl nitrite (2.4 mL, 17.6 mmol) was added in one portion, then 1M TiCl4 CHZCIz solution ( 13.0 mL, 13.0 mmol) was added dropwise at -10 ° C
within a period of 20 min.. After stilling at the same temperature for additional 60 min, the resulting deep-green mixture was poured into ice-cold H20 (100 mL), and stirred for 5-10 min, then extracted with EtOAc {400 mL), and finally ch~ied (Na2S04). Evaporation ofthe solvent under reduced pressure gave an amorphous solid, which was suspended in CHZC12 (50 mL) and collected by filtration. The white solid was waslied with additional CHZClz (3x10 mL) to give dimeric 2-[4'-(a-nitroso)isobutyiylphenyl]propionic acid 6A (0.75 g, 53% yield).

Example II
The ability ofvarious C-nitroso compounds as described below to relax a rabbit aortic ring (smooth muscle) was cam-ied out as described in Stamler, 3., et al., PNAS, Vol. 89, 444-448 (1992).
Results shown in Figs. 1-10 which are tracings of force (tension) in the Y-direction versus time in the X-direction witli downward direction indicating relaxation and upward direction indicating constriction. Concentrations of C-nitroso compound applied at time in the X-direction are indicated as 10'9 (1 nanomolar), 10'6 (1 micromolar), 10'3 (1 milimolar), etc.
"PE" on the figur es means the application of phenylephrine, a constricting agent.
Fig. 1 shows results for Compound (129a) which is a C-nitroso compound obtained by nitrosylating a carbon acid with a pH less than 10. Relaxation effect is shown in Fig. 1 at pM concentration, i.e., at micromolar concentrations.
Fig. 2 shows results for C-nitroso-methylinalonic acid. It is obtained fi~om a carbon acid with a pKa of about 30-35. As shown in fig. 2, it displays relaxation effect at 10 micromolar concentration (very weak activity).
Fig. 3 shows results for C-nitrosobenzene. It is obtained fiom a carbon acid having a pKa of about 45. As shown in Fig 3, it displays no activity at micromolar concentration.
Fig. 4 shows results for C-nitrosophenol. C-Nitrosophenol is obtained from a carbon acid having a pKa greater than 25. As shown in Fig. 4, it displays no activity at micromolar concentrations.
Fig. 5 shows results for the nitrosoketoibuprofen synthesized in Example I. As shown in Fig. 5, it displays relaxation effect at 10 nanomolar concentration.
Fig. 6 shows fiu-ther results for the nitrosoketoibuprofen synthesized in Example I.
Fig. 6 shows the same relaxation effect at 10 nauomolar as does Fig. 7 but not much more activity at higher concentration (since the equilibrium moves in the direction of inactive dimer at higher concentrations).
Fig. 7 shows results for the nitrosoketoibuprofen synthesized in Example I
used in conjunction with 100 p.M glutathione. As shown in Fig. 7, there is no activity because glutathione blocks the activity of the nitrosoketoibuprofen by complexing with it to tie up the NO group (the same occurrence as for dimes); this is a reflection of the C-N(O)R group described above.

Fig. 8 shows more results for the nitrosoketoibuprofen synthesized in Example I.
Relaxation is shown at 1 and 10 nM concentration. This differs some fiomwhat is shown in Figs. 5 and 6 because of the natural variability among blood vessels.
Fig. 9 shows results for 3-methyl-3-nitroso-2,4-petanedione which is obtained fiom a carbon acid with a pKa less than 10. This compound is not water soluble. It displays relaxation effect at concentration greater tlian 10 micromolar and fiu-ther effect at concentration greater than 100 micromolar, but when 100 ~.M glutathione is added it displays relaxation effect at between 1 and 10 nanomolar concentration. The potentiation effect occurs because the C-nitrosodione reacts with glutatliione to fomn S-nitrosoglutathione.
Fig. 10 shows results for 2-methyl-2-nitrosopropane. It is obtained fiom a carbon acid having a pKa of about 55 and is not water soluble. It displays no relaxation effect activity at any of the concentrations used.
Example III
A 60-year-old white male with arthritis, esophageal spasm, coronary artery disease, congestive hear failure, impotence and nightly iu-inaiy incontinence develops gastrointestinal upset when administered ibuprofen (400 mg, three times a day). When the drug is changed so that 0.1 % by weight of the chug is administered as the dimeric nitrosoketoibuprofen of Example I, all symptoms are relieved.
Example IV
A 65-year-old male with angina treated with nitroglycerin develops nitrate tolerance.
Nitroglycerin administration is stopped and Compound (135a) is given at 20 p.glmin continuously with relief of angina.
Example V
A 62-year-old white male with severe rheumatoid arthritis presents with myocardial infarction. His nonsteroidal anti-inffammatoiy chug is stopped because of concerns of increased cardiovascular risk. His joint pain becomes debilitating. Celebrex is administered orally twice a day in 200 mg amount except that 0.1 % by weight of the chug is administered as Compound (115) where Rl and RZ are methyl, with relief ofboth joint pain and angina.
When Compound (200) where Rl and R2 are H and X is -CH2 , and Y is S or O is substituted for the Compound (115) in equal amount, relief ofboth joint pain and angina is also obtained.

Example VI
A 65-year-old white male develops chest pain eight days after deployment of a stent in his circumflex coronary artery and restenosis is confi~~n.ed angiographically.
The artery is reopened and a'Nir stent coated with a polymer incorporating a C-nitroso group such that the C-nitroso group is bound to a carbon derived from a carbon acid with a plea between 10 and 25. The patient does well witli resolution of symptoms. Coronary angiography, performed the next year to assess a valvular leak, reveals an unobstructed circumflex coronary artery.
The polymer incorporating C-nitroso group is obtained as follows:
Polyisobutylene copolymer wherein the second monomer is masked amine substituted styrene, is subjected to unmasking of amine reactive functionably and the resulting free amine groups are reacted with o O
r ON
FCC CN O
whereby the succinimide comes offthe C-nitroso compound and the rest ofthe C-nitroso compound forms an amide with the flee amine groups. The resulting polymer is biocompatible and has a weight average molecular weight of about 75,000.
Variations Variations of the above will be obvious to those skilled in the art. Thus, the scope of the invention is defined by the claims.

Claims (46)

WHAT IS CLAIMED IS:

1. A C-nitroso compound having a molecular weight ranging from about 225 to about 1,000 on a monomeric basis wherein a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25.

2. The C-nitroso compound of Claim 1 which is water-soluble.

3. The C-nitroso compound of Claim 2 where a carbon alpha to the nitrosylated carbon is part of a carbonyl group.

4. The C-nitroso compound of Claim 3 which has a molecular weight ranging from about 225 to about 600 on a monomeric basis.

5. The C-nitroso compound of Claim 4 which is obtained by nitrosylation of a carbon acid having a pKa less than about 10.

6. The C-nitroso compound of Claim 4 which is obtained by nitrosylation of a carbon acid having a pKa ranging from about 15 to about 20.

7. The C-nitroso compound of Claim 1 in dimeric form.

8. A C-nitroso compound as defined in Claim 1 which is obtained by uitrosylating a tertiary carbon of a conventional drug or of a conventional drug modified to modify the carbon acid pKa thereof

9. A C-nitroso compound as defined in Claim 2 which is obtained by nitrosylating a tertiary carbon of a conventional drug or a conventional drug modified to modify the carbon acid pKa thereof.

10. A nitroso compound as defined in Claim 3 which is obtained by nitrosylating a tertiary carbon of a conventional drug or of a conventional drug modified to modify the carbon acid pKa thereof.

11. A C-nitroso compound as defined in Claim 4 which is obtained by nitrosylating a tertiary carbon of a conventional drug or of a conventional drug modified to modify the carbon acid pKa thereof.

12. A C-vitroso compound as defined in Claim 5 which is obtained by nitrosylating a tertiary carbon of a conventional drug or of a conventional drug modified to modify the carbon acid pKa thereof.

13. A C-nitroso compound as defined in Claim 6 which is obtained by nitrosylating a tertiary carbon of a conventional drug or of a conventional drug modified to modify the carbon acid pKa thereof

14. A C-nitroso compound as defined Claim 7 which is obtained by nitrosylating a tertiary carbon atom of a conventional drug or of a conventional drug modified to modify the carbon acid pKa thereof where dimerization proceeds spontaneously during isolation of the product of nitrosylation.

15. A C-nitroso compound as defined in Claim 13 where the conventional drug is a nonsteroidal anti-inflammatory drug.

16. A C-nitroso compound as defined in Claim 15 where the nonsteroidal anti-inflammatory drug is ibuprofen.

17. A C-nitroso compound as defined in Claim 16 which is a nitrosoketoibuprofen in dimeric form.

18. The C-nitroso compound of Claim 17 which is dimeric 2-[4'-(.alpha.-nitroso)isobutylphenyl] propionic acid.

19. A C-nitroso compound as defined in Claim 13 where the conventional drug is an analgesic drug.

20. A C-nitroso compound as defined in Claim 13 where the conventional drug is a COX-2 inhibitor.

21. A C-nitroso compound as defined in Claim 13 where the conventional drug is an antianginal drug.

22. A C-nitroso compound as defined in Claim 13 where the conventional drug is an antihypertensive drug.

23. A C-nitroso compound as defined in Claim 13 where the conventional drug is a diuretic drug.

24. A C-nitroso compound as defined in Claim 13 where the conventional drug is an ACE inhibitor.

25. A C-nitroso compound as defined in Claim 13 where the conventional drug is an antihypercholesterolemic/antihyperlipoproteinemic drug.

26. A C-nitroso compound as defined in Claim 13 where the conventional drug is a calcium channel blocker.

27. A C-nitroso compound as defined in Claim 13 where the conventional drug is an antacid.

28. A C-nitroso compound as defined in Claim 13 where the conventional drug is a bronchodilator.

29. A C-nitroso compound as defined in Claim 13 where the conventional drug is an NMDA antagonist/skeletal muscle relaxant drug.

30. A C-nitroso compound as defined in Claim 13 where the conventional drug is an antiproliferation/tubulin binding agent.

31. A C-nitroso compound as defined in Claim 13 where the conventional drug is an antitubercular drug.

32. A C-nitroso compound as defined in Claim 13 where the conventional chug is a CETP inhibitor.

33. A C-nitroso compound as defined in Claim 13 where the conventional drug is an SOD mimetic.

34. A C-nitroso compound as defined in Claim 13 where the conventional drug is xanthine oxidase inhibitor.

35. A biocompatible polymer incorporating a C-nitroso moiety derived from a carbon acid with a pKa less than about 25, having a weight average molecular weight ranging from 50,000 to 500,000.

36. A medical device coated with polymer as claimed in Claim 35.

37. A method of treating a patient with an inflammatory or painful disorder comprising administering to said patient a therapeutically effective amount of a compound as defined in Claim 15 or an aqueous solution thereof.

38. A method of treating a patient with an inflammatory or painful disorder comprising administering to said patient a therapeutically effective amount of a compound as defined in Claim 16 or an aqueous solution thereof.

39. A method of treating a patient with an inflammatory or painful disorder comprising administering to said patient a therapeutically effective amount of a compound as described in Claim 17 or an aqueous solution thereof.

40. A method of treating a patient with an inflammatory or painful disorder comprising administering to said patient a therapeutically effective amount of a compound as defined in Claim 18 or an aqueous solution thereof.

41. A method of treating a patient in need of nitrosoglutathione which comprises administering to said patient a therapeutically effective amount of a compound as claimed in Claim 5 optionally with administration of glutathione.

42. A method for prophylaxis of a patient who is at risk for coagulation or thrombus formation or microbial or viral infection comprising contacting tissue in the area that is at risk with polymer as claimed in Claim 35.

43. The method of Claim 42 where the patient has or is at risk for restenosis.

44. A C-nitrous compound containing the moiety where X is S, O or NR where R is selected from the group consisting of C1-C6 alkyl which is unsubstituted or which is substituted with one or more alcohol, ether, ester or amide groups which contain from 2 to 10 carbon atoms, and has a molecular weight ranging from about 100 to about 1,000.

45. C-Nitroso compounds according to Claim 44 which comprises the structure:
where X is S, O or NR and n ranges from 0 to 4 and the co responding protonated compounds.

46. A COX-2 inhibitor where a tertiary carbon atom and/or a sulfur atom and/or an oxygen atom is nitrosylated.