USO08088935B2

(12) United States Patent (10) Patent No.: US 8,088,935 B2 Pears0n et al. (45) Date of Patent: Jan. 3, 2012

(54) COMPOUNDS AND METHODS FOR THE FOREIGN PATENT DOCUMENTS TREATMENT OF DE 2326227 2, 1974 ES 3983.19 4, 1975 Inventors: James Pearson, Cambridge, MA (US); FR 2196795 3, 1974 (75) FR 2196796 3, 1974 John J. Talley, Somerville, MA (US); FR 2210398 7, 1974 Mark G. Currie, Sterling, MA (US) GB 1297264 11, 1972 GB 1374981 11, 1974 (73) Assignee: Ironwood Pharmaceuticals, Inc., WO O193867 12/2001 Cambridge, MA (US) WO O3O806O7 10, 2003 OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 Wang, 2002, Role of iNOS and eNOS in modulating proximal tubule U.S.C. 154(b) by 1229 days. transport and acid-base balance. Pizza et 1998. Nitric Oxide synthase inhition reduces muscle inflam (21) Appl. No.: 10/587,054 mation. Patrick Vallance 1998. Student BM.J. (22) PCT Fled: Dec. 23, 2004 * cited by examiner (86) PCT NO.: PCT/US2004/043O82 Primary Examiner — Rita Desai S371 (c)(1), (74) Attorney, Agent, or Firm — Heslin Rothenberg Farley (2), (4) Date: Nov. 22, 2006 & Mesiti P.C. (87) PCT Pub. No.: WO2OOS/O63732 (57) ABSTRACT PCT Pub. Date: Jul. 14, 2005 Compounds and methods for the treatment of asthma are disclosed. The methods involve mast cell stabilization (65) Prior Publication Data together with selective inhibition of iNOS. The compounds are combinations of a mast cell inhibiting moiety and an US 2007/O249644 A1 Oct. 25, 2007 inhibitor of iNOS. An example is: Related U.S. Application Data (60) Provisional application No. 60/531,957, filed on Dec. HOOC O O COOH. 23, 2003. (51) Int. C. CO7D 3L/22 (2006.01) A6 IK3I/353 (2006.01) O O ~~ O (52) U.S. Cl...... 549/401; 549/402:514/456 O (58) Field of Classification Search ...... 549/401, 549/402: 514/456 CH O See application file for complete search history. )=NH NH2 (56) References Cited HN U.S. PATENT DOCUMENTS 3,790,580 A 2, 1974 Johnson et al. 2003/O1995.29 A1 10/2003 Garvey et al. 16 Claims, No Drawings US 8,088,935 B2 1. 2 COMPOUNDS AND METHODS FOR THE (1) A neuronal NOS(NOS-1 or nNOS) was originally isolated TREATMENT OF ASTHMA and cloned from nerve tissue in which it is a constitutive enzyme. nNOS produces NO in response to various physi CROSS REFERENCE TO RELATED ological stimuli, such as the activation of membrane recep APPLICATIONS tors, according to a mechanism dependent on calcium and on calmodulin, nNOS-derived NO serves as a neurotransmitter. This application is a 371 filing of PCT International Appli cation No. PCT/US04/43082 filed Dec. 23, 2004, published (2) An inducible NOS(NOS-2 or iNOS) can be induced in in English as WO 2005/063732 on Jul. 14, 2005. PCT/US04/ response to immunological stimuli Such as, for example, 43082 claimed the priority of U.S. Provisional Application 10 cytokines or bacterial antigens in various cells Such as, for 60/531,957 filed Dec. 23, 2033. The disclosures of both are example macrophages, epithelial cells, hepatocytes, glial incorporated herein by reference in their entirety. cells, and other cell types. The activity of this isoform is not regulated by calcium. Once induced, it produces large FIELD OF THE INVENTION 15 amounts of NO over prolonged periods. (3) An endothelial NOS(NOS-3 or eNOS) is constitutive and The invention relates to compounds and methods for the calcium/calmodulin-dependent. It was originally identified in treatment of asthma. The methods involve mast cell stabili vascular endothelial cells, in which it generates NO in zation together with selective inhibition of iNOS. The com response to physiological stimuli such as the activation of pounds are combinations of a mast cell inhibiting moiety and membrane receptors. an inhibitor of iNOS. Nitric oxide produced by eNOS and nNOS plays a critical BACKGROUND OF THE INVENTION role in cellular signaling and acts to control numerous physi ologic functions including vasodilation and bronchodilation Asthma is a chronic airway inflammatory disorder charac 25 in the lung. In the asthmatic lung, eNOS and nNOS are terized by bronchial hyper-reactivity and bronchospasm, downregulated, and thus contribute to edema and bronchoc among other abnormalities. Lungs of asthmatic patients have onstriction. Contemplating the problem of inadequate eNOS increased numbers of inflammatory cells in bronchioalveolar and nNOS activity, in an approach which is the opposite of fluid and in lung tissues. These inflammatory cells include that taken in the present invention, Garvey et al. (US pub eosinophils, basophils, neutrophils, macrophages, and lym 30 lished application 2003/0199529) have attached stimulators phocytes. In asthmatic lungs, the epithelium, including cili of endogenous NO production to mast cell inhibitors. ated columnar epithelial cells, is damaged. IgE-antigen-mast The NO produced in large amounts by the inducible iso cell interactions represent the early molecular and cellular form iNOS is involved in pathological phenomena associated events that cause inflammatory conditions of asthma. 35 with acute and chronic inflammatory processes in a large Mast Cell Stabilizing Agents provide one approach to the variety of tissues and organs. NO is highly reactive and, prophylaxis and/or treatment of asthma. The prototype drug, together with Superoxide, forms peroxynitrite which dam disodium cromoglycate was synthesized in 1965 and was ages tissues. In asthma this results in epithelial cell extrusion, approved in the United States in 1973 as a prophylactic, 40 sloughing, and cessation of cilia function. An excessive pro nonbronchodilating anti-inflammatory drug for the therapy of duction of NO by induction of iNOS thus plays a part in allergic disorder. Cromolyn is an odorless, white, hygro degenerative pathologies with inflammatory components, scopic crystalline powder that is freely soluble in water up to Such as asthma. 5%. Animal and human studies show it to be excreted In conditions in which an overproduction of NO is delete unchanged in bile and urine. When inhaled into the pulmo 45 rious, it would be desirable to reduce the production of NO by nary tree, as for treatment of asthma, only about 8% of a dose administering substances capable of inhibiting iNOS. How is deposited in the lung and absorbed. Peak plasma levels ever, given the important physiological roles played by the occur within 15 minutes, the biologic half-life is 46-99 min constitutive isoforms, selective inhibition of iNOS is utes. Oral administration in humans results in approximately required. 1% being systemically absorbed. Cromolyn toxicity studies 50 show an impressively low order of acute toxicity, and adverse effects tend to be minimal and reversible. Cromolyn has a SUMMARY OF THE INVENTION unique, purely prophylactic action with no intrinsic bron chodilator or antihistaminic activity. was intro 55 In a composition aspect, the invention relates to agents for duced Subsequent to cromolyn. It is the other standard mast treating a pulmonary disorder represented by the structure: cell stabilizer used in the treatment of asthma. Its chemical properties and therapeutic characteristics are similar. Nitric oxide (NO) is a diffusible radical involved in many physiological and pathological processes. It is synthesized in 60 G)--G) Vivo by oxidation of L-arginine. The synthesis is catalyzed by a family of enzymes known as nitric oxide synthases or NO wherein synthases (NOSs), which are referenced in the international A is a mast-cell stabilizer; enzyme nomenclature system under the number 65 E.C.1.14.13.39. Three NOS isoforms, two of which are con L is a covalent linkage; stitutive and one inducible, are known: B is an iNOS inhibitor. US 8,088,935 B2 3 4 Examples of Such agents are compounds of formula I or II G)--G) In a second method aspect, the invention relates to a method for treating a pulmonary disorder comprising co administering a mast-cell stabilizer and an iNOS inhibitor in the form of a salt, in which one of the mast-cell stabilizer and the iNOS inhibitor is a cation or dication, and the other is an anion ordianion.

DETAILED DESCRIPTION OF THE INVENTION 15 Agents for treating a pulmonary disorder according to the invention are represented by the structure:

II 2O G)--G)

In one embodiment, L is chosen from —CONH , CONH- and —(C=O)OCH(R)O(C=O) and the com pound is represented by a structure chosen from:

wherein R" and Rare chosen from hydroxy, C.C.C.C.C.s, and C. straight and branched alkoxy, -G-O(C=O)R. R. NHR, OR7 and OX", wherein X" is a pharmaceu tically acceptable cation; 35 losso —O(C=O)R’ is the deshydrogen residue of a carboxylic acid, the parent of which, RCOOH, is an inhibitor of . Grro ro inducible nitric oxide synthase (iNOS); —(C=O)R’ is the deshydroxy residue of a carboxylic acid, the parent of which, RCOOH, is an inhibitor of iNOS; 45 G) Grr. O R is - O R' U, wherein U is chosen from hydrogen, O O G)—o (1,2-dithiolan-3-yl) and phenyl, and R' is a divalent C to r and Coalkane or Oxaalkane residue. O O —NHR is the deshydrogen residue of an amine, the parent of 50 which, RNH is an inhibitor of iNOS; in which A' is a mast-cell stabilizer having a carboxylic acid —OR7 is the deshydrogen residue of an alcohol, the parent of substituent; A is a mast-cell stabilizer having an amine Sub which, ROH, is an inhibitor of iNOS: stituent; A is a mast-cell stabilizer having an alcohol Sub G is a linking moiety cleavable under physiologic conditions. 55 stituent B 1S an iNOS inhibitor having an amine substituent In the compounds of the invention, at least one of R', R B is an iNOS inhibitor having an alcohol substituent; B is an and R must be-G-O(C=O)R. R. NHR, OR7, iNOS inhibitor having a carboxylic acid substituent; and R is (C=O)R, (C=O)-G-O(C=O)R, (C=O)R, hydrogen or methyl. Cromolyn would be an example of a (C=O)NHR' or (C=O)OR7. 60 compound that fell into the categories A" (a mast-cell stabi In another composition aspect, the invention relates to lizer having ac arboxylic acid substituent) and A (a mast-cell stabilizer having an alcohol substituent). Nedocromil would pharmaceutical compositions comprising a pharmaceutically be an example of a compound that fell into category A'. acceptable carrier and a compound as described above. Numerous examples of compounds that fall in categories B", In a method aspect the invention relates to a method for 6's Band B are shown below as examples of parents of R. treating a pulmonary disorder comprising administering a In a particular embodiment, the compound is of formula I compound represented by the structure: or H US 8,088,935 B2

-continued O R1 O R! () or O h

10 NMe2 O I-n- IV OS O

R! 15 N () II O f

NMe2 V

O 21 OCH 25

R1 O OCH In these compounds VI RandR are chosen from hydroxy, C.C.C.C.C.s, and Co 30 N straight and branched alkoxy, -G-O(C=O)R. R. - NHR,--OR and—OX", whereinX" is a pharmaceu N. E R tically acceptable cation; CHS n-r 35

—O(C=O)R’ is the deshydrogen residue of a carboxylic acid, the parent of which, RCOOH, is an inhibitor of inducible nitric oxide synthase (iNOS); 40 —(C=O)R’ is the deshydroxy residue of a carboxylic acid, the parent of which, RCOOH, is an inhibitor of iNOS; R is —O R” U, wherein U is chosen from hydrogen, (1,2-dithiolan-3-yl) and phenyl, and R' is a divalent C to Coalkane or Oxaalkane residue, 45 —NHR is the deshydrogen residue of an amine, the parent of which, RNH is an inhibitor of iNOS; —OR7 is the deshydrogen residue of an alcohol, the parent of which, ROH, is an inhibitor of iNOS: 50 G is a linking moiety cleavable under physiologic conditions. Additional examples of Such compounds include structures III through XI in which the R-groups retain the above defini tions and R' has the same definition as R and R: 55 O O IX

CH O 60 O R1

NMe2 65 RO O III

US 8,088,935 B2 10 -continued 6,344,473; 6,143,790; 5,866,612; 6,369,272: 6,552,052: B20 NH 6,495,544; 6,403,830; 5,629,322: 6,110,930; 6,228,866; 6,274,557; 6,432,947; 6,451,821; 5,449,688; 5,723,451: HN l N1 NH2 5,854.251; 5,863,931; 5,889,056; 5,919,787; 5,945,408; H 5,972,940; 5,981,511; 6,355,689; 6,423,705; 6,586,474 and B21 NH 6,465,686; in US published applications 20030013702: 20020037927, 20020049202; 200301 19826; 20020022631; HN ls S 1N1 NH2 20020198243; 20030064978; 20030195256; 20030207896; B22 10 2003.0109522: 20040087653; in PCT applications WO99/ NH 62875; WO99/628785; WO01/78719, WO01/05748; WO01/

N CH3 14371; WO96/35677; WO96/33175; WO96/15120; WO95/ N? s (CH1 r 11014; WO95/11231; WO95/25717; WO95/24382; WO94/ 15 12165; WO94/14780, WO93/13055; WO02/076395; WO03/ N-NHN 5 HN B23 097163; WO03/097050: WO03/026638; WO00/13709; H3C N WO00/26195; WO00/61126; WO01/001.95: WO01/58867; Cy WO01/74351; WO01/94325; WO02/00648: WO02/50021; S WO93/05775; WO95/13805; WO95/34534; WO96/15120; w WO96/27593; WO98/02555; WO98/37079; WO99/26657; CH3 WO99/46240; WOO4/O12726; WO01/72703; WO95/24832: WO94/12165; WO94/14780; WOO4/106312 and WO03/ One parent of the formula ROH is the iNOS-inhibitory alco 026668 and in European published applications EPO446699; hol B24 described in WO 98/37079 as example 53: 25 EP1299365; EP765308; EP957087 and EP1282413. The rel evant disclosures of all are incorporated herein by reference. The concept of “parent’, as used herein, refers to a com B24 pound, such as B1 30 /S O O N N N NH X Yu- C NH O N 21 OH 35 H Additionally, parents of the formulae RCOOH and RNH ten--- are chosen from the iNOS inhibitors described in U.S. Pat. NH NH2 No. 6,355,689: 40 which is a selective inhibitor of iNOS. When the residue of this parent is attached to a chroman of formula I, one possible resulting structure is 512: 45

NH wherein R is chosen from C to C alkyl, C. to C, 51 2 cycloalkyl, C to Ca hydroxyalkyl and C to Chaloalkyl or 50 U.S. Pat. No. 5,863.931:

CO2H o C COOH 55 O O O O

wherein Q is chosen from —CH-CH=CHCH , 60 -(CH2)V(CH2) -O-, - NR— and -(CH2). T(CH) ; p is 2 or 3; q is 1 or 2; V is S(O); x is 0, 1 or 2: R" is Hor Calkyl; ris 1 or 2; sis 1 or 2; and T is cyclobutyl, in which R is —(C=O)R and —(C=O)R’ is the deshy phenyl or pyridyl. Other iNOS inhibitors useful as parent 65 droxy residue of a carboxylic acid, the parent of which, B1, is structures in the instant invention may be found in U.S. Pat. an inhibitor of iNOS. It will be immediately apparent that B1 Nos. 6,451,821; 5,132,453; 5,830,917; 5,684,008; 6,207,708; could also be attached to I as an amide: US 8,088,935 B2 11 12

508 PBO OH O O CH HOOC O. O N HN={ 5 -o-c-( ) and

O (~~. O DTP OH 10 O N S. in which case R is NHR and NHR is the deshydrogen ~ residue of an amine, the parent of which, B1, is an inhibitor of iNOS. Similarly, alcohols may be attached as esters:

\-N N O u) NCrs 21 O HOOC CCO O O 1--> O OH

In one subgenus, R' and R are chosen from hydroxy, C. In other Subgenera the compounds are dioxo-4H.6H-pyrano C2, Cs, Ca, Cs, and Co straight and branched alkoxy, —R. 35 3.2-gquinolines -NHR,--OR7 and—OX"; and R is chosen from hydro gen, -(C=O)R, -(C=O)R. —(C=O)NHR'' and II —(C=O)OR". Another genus includes compounds of for mula: 40

R1 R2 45 O O O O wherein R' is chosen from hydroxy, Rand—OX; and R is chosen from -G-O(C=O)R, NHR and OR7 or wherein 50 R" is chosen from-G-O(C=O)R, NHR and OR7; and O 1--> O R’ is chosen from hydroxy, Rand—OX. OH Other subgenera include esters of formula in which R" is chosen from -G-O(C=O)R, NHR and 55 RI OR"; and R is chosen from hydroxy, C, C2, Cs, Ca, Cs, and C straight and branched alkoxy, Rand—OX. In another subgenus at least one of R', RandR is -G-O (C=O)R or -(C=O)-G-O(C=O)R’; and G is chosen 60 from —OCH2— and —OCH(CH)—. “G” in these cases forms an acetal of formaldehyde or acetaldehyde with the oxygen of O(C=O)R'. Acetals are particularly suitable as linkers that are readily cleaved under physiological condi tions. 65 R substituents include straight or branched alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms, PBO and DTP: US 8,088,935 B2 13 14 wherein R' and R are chosen from hydroxy, C, C2, Cs, Ca. toxic acids and bases. When the compounds contain a quator Cs, and C straight and branched alkoxy and —OX"; and a basic residue, Suitable pharmaceutically acceptable base esters of formula addition salts for the compounds of the present invention include inorganic acids, organic acids and, in the case of quats, water (which formally furnishes the hydroxide anion). R1 Examples include hydroxide, acetate, benzenesulfonate (be Sylate), benzoate, bicarbonate, bisulfate, carbonate, cam phorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, glycolate, bromide, chloride, isethionate, lactate, 10 maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate. Succinate, Sulfate, tartrate, trifluoroacetate, p-toluenesulfonate, acetamidoben Zoate, adipate, alginate, aminosalicylate, anhydromethyl enecitrate, ascorbate, aspartate, calcium edetate, camphorate, 15 camsylate, caprate, caproate, caprylate, cinnamate, cycla mate, dichloroacetate, edetate (EDTA), edisylate, embonate, estolate, esylate, fluoride, formate, gentisate, gluceptate, glu curonate, glycerophosphate, glycolate, glycolylarsanilate, The compounds described herein may contain one or more hexylresorcinate, hippurate, hydroxynaphthoate, iodide, lac asymmetric centers and may thus give rise to enantiomers, tobionate, malonate, meSylate, napadisylate, napsylate, nico diastereomers, and other Stereoisomeric forms. Each chiral tinate, oleate, orotate, oxalate, oxoglutarate, palmitate, pecti center may be defined, in terms of absolute stereochemistry, nate, pectinate polymer, phenylethylbarbiturate, picrate, as (R)- or (S)-. The present invention is meant to include all pidolate, propionate, rhodanide, salicylate, sebacate, Stearate, Such possible isomers, as well as, their racemic and optically tannate, theoclate, tosylate, and the like. When the com pure forms. Optically active (R)- and (S)-, or (D)- and (L)- 25 pounds contain an acidic residue, Suitable pharmaceutically isomers may be prepared using chiral synthons or chiral acceptable base addition salts for the compounds of the reagents, or resolved using conventional techniques. When present invention include ammonium, metallic salts made the compounds described herein contain olefinic double from aluminum, calcium, lithium, magnesium, potassium, bonds or other centers of geometric asymmetry, and unless Sodium and Zinc or organic salts made from lysine, N,N'- specified otherwise, it is intended that the compounds include 30 dibenzylethylenediamine, chloroprocaine, choline, diethano both E and Z geometric isomers. Likewise, all tautomeric lamine, ethylenediamine, meglumine (N-methylglucamine) forms are also intended to be included. and procaine. Other base addition salts includes those made The graphic representations of racemic, ambiscalemic and from: arecoline, arginine, barium, benethamine, benzathine, scalemic or enantiomerically pure compounds used herein betaine, bismuth, clemizole, copper, deanol, diethylamine, are taken from Maehr.J. Chem. Ed. 62, 114-120 (1985): solid 35 diethylaminoethanol, epolamine, ethylenediamine, ferric, and broken wedges are used to denote the absolute configu ferrous, glucamine, glucosamine, histidine, hydrabamine, ration of a chiral element; wavy lines and single thin lines imidazole, isopropylamine, manganic, manganous, methyl indicate disavowal of any stereochemical implication which glucamine, morpholine, morpholineethanol, N-ethylmor the bond it represents could generate; solid and broken bold pholine, N-ethylpiperidine, piperazine, piperidine, lines are geometric descriptors indicating the relative con 40 polyamine resins, purines, , triethylamine, trim figuration shown but denoting racemic character, and wedge ethylamine, tripropylamine, trolamine, and tromethamine. outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. DEFINITIONS The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and, unless 45 Throughout this specification the terms and Substituents a specific configuration is expressly indicated, the depiction is retain their definitions. not intended to designate a particular configuration; thus a Alkyl is intended to include linear, branched, or cyclic carbon-carbon double bond depicted arbitrarily herein as E hydrocarbon structures and combinations thereof. When not may be Z, E, or a mixture of the two in any proportion. otherwise restricted, the term refers to alkyl of 20 or fewer As used herein, and as would be understood by the person 50 carbons. Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and of skill in the art, the recitation of “a compound is intended 6 carbon atoms. Examples of lower alkyl groups include to include salts and Solvates of that compound. methyl, ethyl, propyl, isopropyl, butyl, S- and t-butyl and the The term “solvate” refers to a compound in the solid state, like. Methyl is preferred. Preferred alkyl and alkylene groups wherein molecules of a suitable solvent are incorporated in are those of Co or below (e.g. C. C. C. C. C. C. C7, Cs. the crystal lattice. A suitable solvent for therapeutic admin 55 Co. Co. C1, C12, C13, C14, C1s, C6, C7, C8, C19, C20). istration is physiologically tolerable at the dosage adminis Cycloalkyl is a subset of alkyl and includes cyclic hydrocar tered. Examples of suitable solvents for therapeutic adminis bon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of tration are ethanol and water. When water is the solvent, the cycloalkyl groups include c-propyl, c-butyl, c-pentyl, nor Solvate is referred to as a hydrate. In general, Solvates are bornyl, adamanty1 and the like. formed by dissolving the compound in the appropriate Sol 60 C to Cao Hydrocarbon includes alkyl, cycloalkyl, alkenyl, vent and isolating the Solvate by cooling or using an antisol alkynyl, aryl and combinations thereof. Examples include vent. The solvate is typically dried or azeotroped under ambi benzyl, phenethyl, cyclohexylmethyl, camphoryl and naph ent conditions. thylethyl. Compounds of formula I may contain basic or acidic resi Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 dues, allowing them to be presented as salts. The term “phar 65 carbonatoms of a straight, branched, cyclic configuration and maceutically acceptable salt” refers to salts whose counter combinations thereof attached to the parent structure through ion (anion) derives from pharmaceutically acceptable non an oxygen. Examples include methoxy, ethoxy, propoxy, iso US 8,088,935 B2 15 16 propoxy, cyclopropyloxy, cyclohexyloxy and the like. the acetals “G”) or through the intermediacy of enzymes in Lower-alkoxy refers to groups containing one to four car the respiratory system, for example by esterases within the bons. alveoli. Oxaalkyl refers to alkyl residues in which one or more The terms “methods of treating or preventing” mean ame carbons (and their associated hydrogens) have been replaced 5 lioration, prevention or relief from the symptoms and/or by oxygen. Examples include methoxypropoxy, 3.6.9-trioxa effects associated with lipid disorders. The term “preventing decyl and the like. The term oxaalkyl is intended as it is as used herein refers to administering a medicament before understood in the art see Naming and Indexing of Chemical hand to forestall or obtund an acute episode. The person of Substances for Chemical Abstracts, published by the Ameri ordinary skill in the medical art (to which the present method 10 claims are directed) recognizes that the term “prevent' is not can Chemical Society, 196, but without the restriction of an absolute term. In the medical art it is understood to refer to 127(a), i.e. it refers to compounds in which the oxygen is the prophylactic administration of a drug to Substantially bonded via a single bond to its adjacent atoms (forming ether diminish the likelihood or seriousness of a condition, and this bonds). Similarly, thiaalkyl and azaalkyl refer to alkyl resi is the sense intended in applicants’ claims. As used herein, dues in which one or more carbons have been replaced by 15 reference to “treatment of a patient is intended to include Sulfur or nitrogen, respectively. Examples include ethylami prophylaxis. noethyl and methylthiopropyl. Throughout this application, various references are Acyl refers to groups of 1,2,3,4, 5, 6, 7 or 8 carbon atoms referred to. The disclosures of these publications in their of a straight, branched, cyclic configuration, Saturated, unsat entireties are hereby incorporated by reference as if written urated and aromatic and combinations thereof, attached to the herein. parent structure through a carbonyl functionality. One or The term “mammal’ is used in its dictionary sense. The more carbons in the acyl residue may be replaced by nitrogen, term “mammal’ includes, for example, mice, hamsters, rats, oxygen or Sulfur as long as the point of attachment to the cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., parent remains at the carbonyl. Examples include formyl. Canis familiaris), cats, rabbits, guinea pigs, and primates, acetyl, propionyl, isobutyryl, t-butoxycarbonyl, benzoyl, 25 including humans. Humans would be the preferred Subjects benzyloxycarbonyl and the like. Lower-acyl refers to groups of the methods of treatment. containing one to four carbons. Terminology related to “protecting”, “deprotecting and Aryl and heteroaryl mean a 5- or 6-membered aromatic or “protected functionalities occurs throughout this applica heteroaromatic ring containing 0-3 heteroatoms selected tion. Such terminology is well understood by persons of skill from O, N, or S; a bicyclic 9- or 10-membered aromatic or 30 in the art and is used in the context of processes which involve heteroaromatic ring system containing 0-3 heteroatoms sequential treatment with a series of reagents. In that context, selected from O, N, or S; or a tricyclic 13- or 14-membered a protecting group refers to a group which is used to mask a aromatic or heteroaromatic ring system containing 0-3 het functionality during a process step in which it would other eroatoms selected from O, N, or S. Aromatic 6- to 14-mem wise react, but in which reaction is undesirable. The protect bered carbocyclic rings include, e.g., benzene, naphthalene, 35 ing group prevents reaction at that step, but may be subse indane, tetralin, and fluorene and the 5- to 10-membered quently removed to expose the original functionality. The aromatic heterocyclic rings include, e.g., imidazole, pyridine, removal or “deprotection’ occurs after the completion of the indole, thiophene, benzopyranone, thiazole, furan, benzimi reaction or reactions in which the functionality would inter dazole, quinoline, isoquinoline, quinoxaline, pyrimidine, fere. Thus, when a sequence of reagents is specified, as it is in pyrazine, tetrazole and pyrazole. 40 the processes of the invention, the person of ordinary skill can Arylalkyl means an alkyl residue attached to an aryl ring. readily envision those groups that would be suitable as “pro Examples are benzyl, phenethyl and the like. tecting groups. Suitable groups for that purpose are dis Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to cussed in standard textbooks in the field of chemistry, such as alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H Protective Groups in Organic Synthesis by T. W. Greene atoms in each residue are replaced with halogen, haloalkyl, 45 John Wiley & Sons, New York, 1991. hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to The abbreviations Me, Et, Ph, Tf, Ts and Ms represent as alkoxycarbonyl), carboxamido (also referred to as alky methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluene laminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, Sulfonyl and methanesulfonyl respectively. For example, in dialkylamino, mercapto, alkylthio. Sulfoxide, Sulfone, acy the tables, OEt refers to ethoxy. A comprehensive list of lamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, ben 50 abbreviations utilized by organic chemists (i.e. persons of Zyloxy, or heteroaryloxy. ordinary skill in the art) appears in the first issue of each The term “halogen' means fluorine, chlorine, bromine or volume of the Journal of Organic Chemistry. The list, which iodine. is typically presented in a table entitled “Standard List of A “quaternary ammonium salt as used herein refers to a Abbreviations” is incorporated herein by reference. substituent of the general formula - NRRRX, in which 55 The invention also encompasses pharmaceutical composi R’ is C, to Co. hydrocarbon or forms a five- to seven-mem tions comprising a pharmaceutically acceptable carrier and bered ring with R: R is alkyl or forms a five- to seven the foregoing compounds. One embodiment of the invention membered ring with R: R is alkyl or together with R7 or R includes aerosol pharmaceutical compositions. Another forms a second five- to seven-membered ring; and X is an embodiment of the invention includes oral formulations anion. 60 including tablets, capsules and syrups. The term “prodrug” refers to a compound that is made While it may be possible for the compounds to be admin more active in vivo. Commonly the conversion of prodrug to istered as the raw chemical, it is preferable to present them as drug occurs by enzymatic processes in the liver or blood of the a pharmaceutical composition. According to a further aspect, mammal. Many of the compounds of the invention may be the present invention provides a pharmaceutical composition chemically modified without absorption into the systemic 65 comprising a compound as described above, or a pharmaceu circulation, and in those cases, activation in Vivo may come tically acceptable salt or solvate thereof, together with one or about by chemical action (as in the acid-catalyzed cleavage of more pharmaceutically carriers thereof and optionally one or US 8,088,935 B2 17 18 more other therapeutic ingredients. The carrier(s) must be intranasal applications. Aerosols may be conveniently pre “acceptable' in the sense of being compatible with the other sented in unit dosage form and prepared by any of the meth ingredients of the formulation and not deleterious to the ods well-known in the art of pharmacy. Aerosol formulations recipient thereof. are stable dispersions or Suspensions of Solid material and The formulations include those suitable for oral, parenteral liquid droplets in a gaseous medium and can be placed into (including Subcutaneous, intradermal, intramuscular, intrave pressurized acceptable propellants, such as hydrofluoroal nous and intraarticular), rectal and topical (including dermal, kanes (HFAs, i.e. HFA-134a and HFA-227, or a mixture buccal, Sublingual and intraocular) administration. The most thereof), dichlorodifluoromethane (or other chlorofluocarbon Suitable route may depend upon the condition and disorder of propellants such as a mixture of Propellants 11, 12, and/or the recipient. The formulations may conveniently be pre 10 114), propane, nitrogen, and the like. Pulmonary formula sented in unit dosage form and may be prepared by any of the tions may include permeation enhancers such as fatty acids, methods well known in the art of pharmacy. In general, the and saccharides, chelating agents, enzyme inhibitors (e.g., formulations are prepared by uniformly and intimately bring protease inhibitors), adjuvants (e.g., glycocholate, Surfactin, ing into association the active ingredient with liquid carriers span 85, and nafamo.stat), preservatives (e.g., benzalkonium or finely divided solid carriers or both and then, if necessary, 15 chloride or chlorobutanol), and ethanol (normally up to 5% shaping the product into the desired formulation. but possibly up to 20%, by weight). Ethanol is commonly Formulations of the present invention suitable for oral included in aerosol compositions as it can improve the func administration may be presented as discrete units such as tion of the metering valve and in Some cases also improve the capsules, cachets or tablets each containing a predetermined stability of the dispersion. Pulmonary formulations may also amount of the active ingredient; as a powder or granules; as a include surfactants, which include but are not limited to bile Solution or a suspension in an aqueous liquid or a non-aque salts and those described in U.S. Pat. No. 6,524,557 and ous liquid; or as an oil-in-water liquid emulsion or a water references therein. The surfactants described in U.S. Pat. No. in-oil liquid emulsion. The active ingredient may also be 6,524,557, e.g., a C8-C16 fatty acid salt, a bile salt, a phos presented as a bolus, electuary or paste. pholipid, or alkyl saccharide are advantageous in that some of A tablet may be made by compression or molding, option 25 them also reportedly enhance absorption of the compound in ally with one or more accessory ingredients. Compressed the formulation. tablets may be prepared by compressingina Suitable machine Also suitable in the invention are dry powder formulations the active ingredient in a free-flowing form Such as a powder comprising a therapeutically effective amount of active com or granules, optionally mixed with a binder, lubricant, inert pound blended with an appropriate carrier and adapted for use diluent, lubricating, Surface active or dispersing agent. 30 in connection with a dry-powder inhaler. Absorption enhanc Molded tablets may be made by molding in a suitable ers which can be added to dry powder formulations of the machine a mixture of the powdered compound moistened present invention include those described in U.S. Pat. No. with an inert liquid diluent. The tablets may optionally be 6,632,456. WO 02/080884 describes new methods for the coated or scored and may be formulated so as to provide Surface modification of powders. Aerosol formulations may Sustained, delayed or controlled release of the active ingredi 35 include U.S. Pat. No. 5,230,884, U.S. Pat. No. 5,292,499, WO ent therein. 017/8694, WO 01/78696, U.S. 2003019437, U.S. The pharmaceutical compositions may include a “pharma 20030165436, and WO 96/40089 (which includes vegetable ceutically acceptable inert carrier, and this expression is oil). Sustained release formulations suitable for inhalation are intended to include one or more inert excipients, which described in U.S. 20010036481A1, 20030232019A1, and include starches, polyols, granulating agents, microcrystal 40 U.S. 20040018243A1 as well as in WO 01/13891, WO line cellulose, diluents, lubricants, binders, disintegrating 02/067902, WO 03/072080, and WO 03/079885. Pulmonary agents, and the like. If desired, tablet dosages of the disclosed formulations containing microparticles are described in WO compositions may be coated by Standard aqueous or non 03/015750, U.S. 20030008013, and WO 00/00176. Pulmo aqueous techniques, "Pharmaceutically acceptable carrier nary formulations containing stable glassy state powder are also encompasses controlled release means. 45 described in U.S. 2002014 1945 and U.S. Pat. No. 6,309,671. Compositions of the present invention may also optionally Other aerosol formulations are described in EP 1338272A1 include other therapeutic ingredients, anti-caking agents, pre WO 90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436, servatives, Sweetening agents, colorants, flavors, desiccants, 367, WO 91/04011, and U.S. Pat. No. 6,294,153 and U.S. Pat. plasticizers, dyes, and the like. Any such optional ingredient No. 6,290,987 describes a liposomal based formulation that must, of course, be compatible with the compound of the 50 can be administered via aerosol or other means. Powder for invention to insure the stability of the formulation. mulations for inhalation are described in U.S. 2003.0053960 The agents, alone or in combination with other Suitable and WO 01/60341. The agents can be administered intrana components, can be administered by pulmonary route utiliz sally as described in U.S. 20010038824. ing several techniques including but not limited to intratra While the pulmonary route is advantageous in most cheal instillation (delivery of solution into the lungs by 55 instances, there may also be instances in which other routes of Syringe), intratracheal delivery of liposomes, insufflation (ad administration may be advantageous. For example, oral ministration of powder formulation by Syringe or any other administration may be desirable. In that regard, one may similar device into the lungs) and aerosol inhalation. Formu contemplate administration using a formulation in which the lations suitable for pulmonary route inhalation include sterile compound is releasably encapsulated by modified amino Solutions for nebulization comprising a therapeutically effec 60 acids, as described in U.S. Pat. No. 5,811,127. One may also tive amount of the compound dissolved in aqueous saline contemplate administration as an implantable Sustained-re Solution and optionally containing a preservative Such as lease dosage form, Such as described in US published appli benzalkonium chloride or chlorobutanol, and aerosol formu cation 200401 15236. lations comprising a therapeutically effective amount dis The dose range for adult humans is generally from 0.005 Solved or Suspended in an appropriate propellant. Aerosols 65 mg to 10 g/day orally. Tablets or other forms of presentation (e.g., jet or ultrasonic nebulizers, metered-dose inhalers provided in discrete units may conveniently contain an (MDIs), and dry-powder inhalers (DPIs)) can also be used in amount of compound of the invention which is effective at US 8,088,935 B2 19 Such dosage or as a multiple of the same, for instance, units -continued containing 5 mg to 500 mg, usually around 10 mg to 200 mg. NH2 The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, 3 the dose employed will depend on a number of factors, N-1\s CO2H including the age and sex of the patient, the precise disorder NH' being treated, and its severity.

The invention also relates to methods for preventing and/or H treating pulmonary disorders. According to the invention one 10 may administer a compound as described above for treating "> NH2 bronchospasm, for inducing bronchodilation, for treating NH' chronic obstructive pulmonary disease (including chronic bronchitis with normal airflow), for treating asthma (includ ing allergen-induced asthma, viral-induced asthma, cold-in 15 HN duced asthma, pollution-induced asthma and exercise-in duced asthma) and for treating rhinitis (including allergic HN2 N CHE a sco rhinitis). N A broad spectrum of respiratory diseases and disorders O HN1 V have been recognized, many of which have overlapping and interacting etiologies. One of the most widespread and preva lent of these diseases in western populations is the chronic disease referred to as "asthma. Other such disorders are also characterized by acute pulmonary vasoconstriction Such as 25 may result from pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis inflam mation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, post-cardiac Sur gery, acute pulmonary hypertension, persistent pulmonary 30 hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembo lism, herapin-protamine reactions, sepsis, status asthmaticus or hypoxia (including iatrogenic hypoxia) and other forms of reversible pulmonary vasoconstriction. Such pulmonary dis 35 orders also are also characterized by inflammation of the lung including those associated with the migration into the lung of nonresident cell types including the various leucocyte Sub classes. Also included in the respiratory disorders contem plated are: bullous disease, pigeon fancier's disease, asth 40 matic bronchitis, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, farmer's lung, allergic eye diseases (including allergic conjunctivitis, Vernal conjunctivitis, Vernal keratoconjunctivitis, and giant papil lary conjunctivitis), and cystic fibrosis and other diseases 45 which are characterized by inflammation of the lung and/or excess mucosal Secretion. Other physiological events which are contemplated to be controlled include platelet activation in the lung. 50 The methods for treating pulmonary disorders also encom pass co-administering a mast-cell stabilizer and an iNOS inhibitor in the form of a salt, in which one of the mast-cell stabilizer and the iNOS inhibitor is a cation or dication, and the other is an anion ordianion. 55 Cations include:

H " --~~ 60 NH' NH2 HC3 n-1\s COH2 MV 65 NH' O O NH, US 8,088,935 B2 21 22 -continued -continued

CH3 O O H N 2 CII . . C y NH -- 5 N NH" 2 S HO H N NH' "HN N n N NH' NH' | 2N 10 2 N l CH S. NH HN s1 CH3 and their corresponding dianions. NH' NH' The invention also encompasses the salts themselves. 15 Combination therapy can be achieved by administering l Y NH2 NH HN N HN s1N1 2 two or more agents, each of which is formulated and admin CH3 NH' istered separately, or by administering two or more agents in NH2 a single formulation. Other combinations are also encom Y" passed by combination therapy. For example, two agents can is-s-s-sN COOH be formulated together and administered in conjunction with H a separate formulation containing a third agent. While the two or more agents in the combination therapy can be adminis ". NH2 tered simultaneously, they need not be. For example, admin NH' 1sD COOH 25 istration of a first agent (or combination of agents) can pre H H cede administration of a second agent (or combination of -N N COOH agents) by minutes, hours, days, or weeks. Thus, the two or HN r n-n-n more agents can be administered within minutes of each other NH' NH2 or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or 30 within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6,7,8,9, or 10 weeks of each other. In some cases even longer intervals are possible. While in many cases N S-1a N/ it is desirable that the two or more agents used in a combina tion therapy be present in within the patient’s body at the 35 same time, this need not be so. Combination therapy can also include two or more administrations of one or more of the F CrF agents used in the combination. For example, if agent X and NH agent Y are used in a combination, one could administer them CH sequentially in any combination one or more times, e.g., in the N 3 40 order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc. The compounds of the present invention can be coadmin \ SrrScir.NH O HNG) istered with any of the following: (1) B-agonists including but not limited to: albuterol (Proventil(R), (R), Vento lin R), , bitoterol, , , formot and their corresponding dications. Anions include: 45 erol, isoetharine (Bronkosol(R), BronkometerR), metaproter enol (Alupent(R), MetaprelR), (Maxair(R), , , , (Brethaire(R), HO O Brethine(R), Bricanyl(R), adrenalin, isoproterenol (Isuprel(R), epinephrine bitartrate (PrimateneR), ephedrine, orciprenline, 50 fenoterol and isoetharine; (2) Steroids, including but not lim ited to beclomethasone, beclomethasone dipropionate, , , bunedoside, butiXocort, dexam ethasone, , fluocortin, fluticasone, hydrocortisone, methyl prednisone, , predonisolone, predo 55 nisone, tipredane, tiXocortal, , and triamcino lone acetonide; (3) B-agonist-corticosteroid combinations e.g., salmeterol-fluticasone (AdvairR), -budes onid (Symbicort(R); (4) leukotriene D4 receptor antagonists/ leukotriene antagonists/LTD4 antagonists (i.e., any com 60 pound that is capable of blocking, inhibiting, reducing or otherwise interrupting the interaction between leukotrienes and the Cys LTI receptor) including but not limited to: , , montelukast sodium (Singulair R), , iralukast, pobilukast, SKB-106,203 and com 65 pounds described as having LTD4 antagonizing activity described in U.S. Pat. No. 5,565,473; (5) 5-lipoxygenase inhibitors and/or leukotriene biosynthesis inhibitors e.g. US 8,088,935 B2 23 24 and BAY1005 (CA registry 128253-31-6); (6) his in means-plus-function terms. In other words, O(C=O)R’ tamine H1 receptor antagonists/antihistamines (i.e. any com is the deshydrogen residue of a carboxylic acid, the parent pound that is capable of blocking, inhibiting, reducing or of which, RCOOH, is a chemical means for inhibiting otherwise interrupting the interaction between histamine and inducible nitric oxide synthase (iNOS); its receptor) including but not limited to: astemizole, acrivas —(C=O)R’ is the deshydroxy residue of a carboxylic acid, tine, antazoline, azatadine, azelastine, astamizole, bromophe the parent of which, RCOOH, is a chemical means for niramine, bromopheniramine maleate, carbinoxamine, care inhibiting iNOS: bastine, cetirizine, chlorpheniramine, chloropheniramine maleate, cimetidine, clemastine, cyclizine, cyproheptadine, NHR is the deshydrogen residue of an amine, the parent of descarboethoxyloratadine, dexchlorpheniramine, dimethin 10 which, R'NH2, is a chemical means for inhibiting iNOS; dene, diphenhydramine, diphenylpyraline, doxylamine Suc —OR7 is the deshydrogen residue of an alcohol, the parent of cinate, doxylamine, ebastine, efletirizine, epinastine, famoti which, ROH, is a chemical means for inhibiting iNOS. dine, fexofenadine, hydroxy Zine, hydroxy Zine, ketotifen, Chemical means for inhibiting iNOS are compounds (i.e. levocabastine, levocetirizine, levocetirizine, loratadine, 15 chemicals) that exhibit ICso below 25uM when tested against meclizine, mepyramine, meduitazine, methdilazine, human iNOS according to the method of Moore et al. J. Med. mianserin, mizolastine, noberastine, norasternizole, noraZ Chem. 39, 669-672 (1996). Examples of many such com temizole, phenindamine, pheniramine, picumast, promethaZ pounds are shown above as B1 through B24. In one embodi ine, pynlamine, pyrilamine, ranitidine, temelastine, terfena ment, inhibitors are those with ICso below 10 uM. In another dine, trimeprazine, tripelenamine, and triprolidine; (7) an embodiment, inhibitors are those with an ICso below 5uM. including but not limited to: atropine, benz For the purpose of the invention, iNOS inhibitors should be tropine, biperiden, flutropium, hyoscyamine, ilutropium, Selective for iNOS over eNOS and nNOS. Selective means ipratropium, , methScopolamine, oxybu having an ICso against iNOS that is no more than /io" the tinin, rispenzepine, Scopolamine, and tiotropium; (8) an anti ICs against nNOS and eNOS as measured by the method tussive including but not limited to: dextromethorphan, 25 described in Moore (op. cit.) Unless some other meaning is codeine, and hydromorphone; (9) a decongestant including clear from its context, the term “iNOS inhibitor, not further but not limited to: pseudoephedrine and phenylpropanola modified, as used herein refers to a selective iNOS inhibitor. mine; (10) an expectorant including but not limited to: guafenesin, guaicolsulfate, terpin, ammonium chloride, glyc The compounds of the present invention may possess one 30 or more of the following advantages: they lessen bronchial erol guaicolate, and iodinated glycerol; (11) a bronchodilator epithelial damage in asthma; they exhibit improved stability, including but not limited to: and : formulation and manufacturing characteristics; they possess (12) an anti-inflammatory including but not limited to: improved pharmacokinetic properties, allowing in many fluribiprofen, diclophenac, indomethacin, ketoprofen, S-ket roprophen, tenoxicam; (13) a PDE inhibitor including but not cases, once or twice daily inhaled dosing; they offer an alter limited to filaminast, denbufyllene , , 35 native to steroid therapy , and ; (14) a recombinant humanized The efficacy of the compounds of the invention may be monoclonal antibody e.g. Xolair (also called ), demonstrated in a test that measures airway hyperresponsive rhuMab, and talizumab; and (14) a humanized lung Surfac ness see Muijsers et al. Br. J. Pharmacol. 134, 434 (2001); tant e.g. Surtaxin R, formerly known as disc-104 (Discovery 40 Elwood et al. Am. Rev. Respir. Dis. 145, 1289-1294 (1992) Laboratories). and Eynott et al. Eur: J. Pharm. 452, 123 (2002) or in a test Finally one may describe the compounds of formula I or II that measures inflammation in an airway see Chen et al. Acta Pharmacol. Sin. 24, 697 (2003). The activity of the com I pounds of the invention can be tested in the presence or absence of serum. In the presence of serum, one would expect 45 both iNOS activity and mast cell stabilization activity, which can be assayed in methods described by Misko et al. Eur: J. Pharmacol. 233, 119-125 (1993) and Kusner et al. J. Phar macol. Exp. Ther: 184, 41-46 (1973) respectively. In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifica tions thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in II 55 themselves known, but are not mentioned here. In Scheme I disodium chromylglycate 1 is treated with one equivalent of an alkyl halide in a dipolar aprotic solvent Such as dimethylformamide (DMF) to provide the corresponding 60 mono-ester 2. Typically, this procedure also produces some diester 3, wherein R1 =R2 and unreacted 1. After separation of the mono-ester 2 it can be converted into diester 3 by reaction with an alkylhalide in a dipolar aprotic solvent to provide the diester 3. The diester 3 is then condensed with an appropri 65 ately protected acid, such as an N-Boc-amino acid inhibitor of iNOS, in the presence of a dehydrating agent, Such as 1,3- dicyclohexylcarbodiimide (DCC), to provide the protected US 8,088,935 B2 25 26 ester. The protecting group is then removed to provide the -continued desired chromyl iNOS inhibitors 4. In the case of an N-Boc amino acid, the protecting group can be removed by an acid OR OR such as HCl in dioxane. O O 5 O O 1) N-Boc-AA -- 2) HCI Scheme I O ar^. O ONa ONa OH 10 3 O O O O RX OR OR Her O O O arr. O 15 O O OH 1

2O O O~~ O OR ONa O O O y R3 O O RX O NY- 4 25 O arr. O In Scheme II disodium chromylglycate 1 is treated with OH one equivalent the chloromethyl ester of a protected iNOS 2 inhibitor such as 5 to provide, after purification, the corre sponding ester. The ester is then deprotected to afford the desired chromyl iNOS inhibitor 6.

ONa ONa

H P N H O O O O s 5

ONa O O

s H NH

OH US 8,088,935 B2 27 28 Scheme III illustrates the method for the preparation of mono-ester amide derivatives 8. The route commences with the coupling of an orthogonally protected ester of an iNOS inhibitor 7 with the mono-ester 2 in the presence of a amide coupling agent such as 1,3-dicyclohexylcarbodiimide. The resulting amide derivative is then converted into the desired analogues 8 by removal of the ester of the iNOS moiety. The ester moiety of the iNOS inhibitor can be such things as the tert-butyl ester, the beta-trimethylsilylethyl ester, para-meth 10 oxybenzyl ester, and the like. If the iNOS inhibitor compo nent does not possess an acid Substituent then the amine can be coupled directly to 2 without the need for protection and deprotection. If the desired product is the free acid of 8 (R'=H) the route can be to saponify the ester of 8, or to 15 couple one equivalent of the protected iNOS inhibitor 7 with 1 followed by removal of the protecting groups.

OR ONa

OR O 1. CH

OH

Illustrated in Scheme IV is the method used for the prepa Compounds that are representative of the invention are ration of bis-iNOS amides of chromyln. The method involves shown in Tables 1 and 2 below. In these tables the numbers coupling of 1 with the ester protected iNOS inhibitor- - - - - moiety 45 and abbreviations refer to structures presented above. Thus, 7 in the presence of a dehydrating agent such as 1,3-dicyclo heXVlcarbodiimideexylcarbod11m1de tto produceduce unethe esterest protectedtected vers1on o f for example, the compound of example 111 in Table 1 is 9, R=ester. In a subsequent step the ester moiety is converted described as an amide of B1 and an ester of PBO attached to to the corresponding acid, 9, R=H, by Saponification. Suit- the nedocromil core. The structure of the compound would able esters are those listed in Scheme III. be:

Scheme IV 1 + 7 -- NH COR O O COR NH

H3C ul N ~- N O O N 1N1-S-1a N lsCH3

O O~~. OH US 8,088,935 B2 29 30

111

O-(CH)

In all of the compounds in the tables, when an amide is 15 formed, it is formed from the primary O-amine when R' or R is an O-amino acid (B1-B3, B5, B7-B13), and from the pri mary amine oramidine in the other cases (B4, B6, B14-B19, B22, B23). When the residue is B20, the point of attachment is on the terminal nitrogen of the hydrazine; when the residue is B21, the point of attachment is the primary amine. The entry “acetal in the columns headed “linkage” refer to acetals of formaldehyde, i.e. —OCHO . Thus the com pound of example 518 in Table 2 has the structure:

518 SNs

O

O

O

NH

N ls H CH

45 TABLE 1. TABLE 1-continued

Example # linkage R2 linkage Example # linkage R2 linkage

1OO ester - OH na 60 108 B1 amide - OH 101 ester - OEt ester 109 B1 amide - OEt ester 102 ester DTP ester 110 B1 amide DTP ester 103 ester PBO ester 111 B1 amide PBO ester 104 acetal - OH na 112 - OH na B1 ester 105 acetal - OEt ester 113 - OEt ester B1 ester 106 acetal DTP ester 65 114 DTP ester B1 ester 107 acetal PBO ester 115 PBO ester B1 ester US 8,088,935 B2 31 32 TABLE 1-continued TABLE 1-continued

O O O O

Example # linkage R2 linkage Example # linkage R2 linkage

16 na acetal 15 8O ester 17 ester acetal 81 ester - OEt ester 18 DTP ester acetal 82 ester DTP ester 19 PBO ester acetal 83 ester PBO ester 2O na amide 84 acetal 21 - OEt ester amide 85 acetal - OEt ester 22 DTP ester amide 86 acetal DTP ester 23 PBO ester amide 87 acetal PBO ester 24 B2 ester na 88 amide 25 B2 ester - OEt ester 89 amide ester 26 B2 ester DTP ester 90 amide ester 27 B2 ester PBO ester 91 amide ester 28 B2 acetal na 92 na ester 29 B2 acetal - OEt ester 25 93 - OEt ester ester 30 B2 acetal DTP ester 94 DTP ester ester 31 B2 acetal PBO ester 95 PBO ester ester 32 B2 amide na 96 na acetal 33 B2 amide - OEt ester 97 - OEt ester acetal 34 B2 amide DTP ester 98 DTP ester acetal 35 B2 amide PBO ester 30 99 PBO ester acetal 36 na B2 ester 2OO na amide 37 –OEt ester B2 eSter 2O1 –OEt eSter amide 38 DTP ester B2 ester 2O2 DTP ester amide 39 PBO ester B2 ester 2O3 PBO ester amide 40 na B2 acetal 204 B6 amide 41 - OEt ester B2 acetal 35 205 B6 amide - OEt ester 42 DTP ester B2 acetal 2O6 B6 amide DTP ester 43 PBO ester B2 acetal 2O7 B6 amide PBO ester 44 na B2 amide 208 na B6 amide 45 - OEt ester B2 amide 209 ester B6 amide 46 DTP ester B2 amide 210 ester B6 amide 47 PBO ester B2 amide 40 211 ester B6 amide 48 B3 ester na 212 ester 49 B3 ester - OEt ester 213 ester - OEt ester 50 B3 ester DTP ester 214 ester DTP ester 51 B3 ester PBO ester 215 ester PBO ester 52 B3 acetal na 216 acetal 53 B3 acetal - OEt ester 217 acetal - OEt ester S4 B3 acetal DTP ester 45 218 acetal DTP ester 55 B3 acetal PBO ester 219 acetal PBO ester 56 B3 amide na 220 amide 57 B3 amide - OEt ester 221 amide - OEt ester 58 B3 amide DTP ester 222 amide DTP ester 59 B3 amide PBO ester 223 amide PBO ester 60 na B3 ester 50 224 na B7 ester 61 - OEt ester ester 225 - OEt eSe ester 62 DTP ester ester 226 DTP eSe ester 63 PBO ester ester 227 PBO eSe ester 64 na acetal 228 na acetal 65 - OEt ester acetal 229 - OEt eSe acetal 66 DTP ester acetal 55 230 DTP eSe acetal 67 PBO ester acetal 231 PBO eSe acetal 68 - OH na amide 232 - OH na amide 69 - OEt ester amide 233 - OEt eSe amide 70 DTP ester amide 234 DTP eSe amide 71 PBO ester B3 amide 235 PBO eSe B7 amide 72 B4 amide - OH na 60 236 B8 eSe - OH 73 amide - OEt ester 237 eSe - OEt ester 74 amide DTP ester 238 eSe DTP ester 75 B4 amide PBO ester 239 eSe PBO ester 76 - OH na B4 amide 240 acetal - OH 77 - OEt ester amide 241 acetal - OEt ester 78 DTP ester amide 65 242 acetal DTP ester 79 PBO ester amide 243 acetal PBO ester US 8,088,935 B2 33 34 TABLE 1-continued TABLE 1-continued

O O O O

Example # R1 linkage R2 linkage Example # R1 linkage R2 linkage

244 B8 amide - OH na 15 3O8 B1 ester - OH na 245 B8 amide - OEt ester 309 B1 ester - OEt ester 246 B8 amide DTP ester 310 B1 ester DTP ester 247 B8 amide PBO ester 311 B1 ester PBO ester 248 - OH na B8 ester 312 B1 acetal - OH na 249 - OEt ester B8 ester 313 B1 acetal - OEt ester 250 DTP ester B8 ester 2O 314 B1 acetal DTP ester 251 PBO ester B8 ester 315 B1 acetal PBO ester 252 - OH na B8 acetal 316 B1 amide - OH na 253 - OEt ester B8 acetal 317 B1 amide - OEt ester 2S4 DTP ester B8 acetal 318 B1 amide DTP ester 255 PBO ester B8 acetal 319 B1 amide PBO ester 2S6 - OH na B8 amide 32O - OH na B1 ester 257 - OEt ester B8 amide 25 321 - OEt ester B1 ester 258 DTP ester B8 amide 322 DTP ester B1 ester 259 PBO ester B8 amide 323 PBO ester B1 ester 260 B9 ester - OH na 324 - OH na B1 acetal 261 B9 ester - OEt ester 325 - OEt ester B1 acetal 262 B9 ester DTP ester 326 DTP ester B1 acetal 263 B9 ester PBO ester 30 327 PBO ester B1 acetal 264 B9 acetal - OH na 328 - OH na B1 amide 265 B9 acetal –OEt eSter 329 –OEt eSter B1 amide 266 B9 acetal DTP ester 330 DTP ester B1 amide 267 B9 acetal PBO ester 331 PBO ester B1 amide 268 B9 amide - OH na 332 B12 ester - OH na 269 B9 amide - OEt ester 35 333 B12 ester - OEt ester 270 B9 amide DTP ester 334 B12 ester DTP ester 271 B9 amide PBO ester 335 B12 ester PBO ester 272 - OH na B9 ester 336 B12 acetal - OH na 273 - OEt ester B9 ester 337 B12 acetal - OEt ester 274 DTP ester B9 ester 338 B12 acetal DTP ester 275 PBO ester B9 ester 40 339 B12 acetal PBO ester 276 - OH na B9 acetal 340 B12 amide - OH na 277 - OEt ester B9 acetal 341 B12 amide - OEt ester 278 DTP ester B9 acetal 342 B12 amide DTP ester 279 PBO ester B9 acetal 343 B12 amide PBO ester 28O - OH na B9 amide 344 - OH na B12 ester 281 - OEt ester B9 amide 345 - OEt ester B12 ester 282 DTP ester B9 amide 45 346 DTP ester B12 ester 283 PBO ester B9 amide 347 PBO ester B12 ester 284 B10 ester - OH na 348 - OH na B12 acetal 285 B10 ester - OEt ester 349 - OEt ester B12 acetal 286 B10 ester DTP ester 350 DTP ester B12 acetal 287 B10 ester PBO ester 351 PBO ester B12 acetal 288 B10 acetal - OH na 50 352 - OH na B12 amide 289 B10 acetal - OEt ester 353 - OEt ester B12 amide 290 B10 acetal DTP ester 3S4 DTP ester B12 amide 291 B10 acetal PBO ester 355 PBO ester B12 amide 292 B10 amide - OH na 356 B13 ester - OH na 293 B10 amide - OEt ester 357 B13 ester - OEt eSter 294 B10 amide DTP ester 55 358 B13 ester DTP eSter 295 B10 amide PBO ester 359 B13 ester PBO eSter 296 - OH na B10 ester 360 B13 acetal - OH na 297 - OEt ester B10 ester 361 B13 acetal - OEt eSter 298 DTP ester B10 ester 362 B13 acetal DTP eSter 299 PBO ester B10 ester 363 B13 acetal PBO eSter 3OO - OH na B10 acetal 60 364 B13 amide - OH na 301 - OEt ester B10 acetal 365 B13 amide - OEt eSter 3O2 DTP ester B10 acetal 366 B13 amide DTP eSter 303 PBO ester B10 acetal 367 B13 amide PBO eSter 3O4 - OH na B10 amide 368 - OH na B13 eSter 305 - OEt ester B10 amide 369 - OEt ester B13 eSter 306 DTP ester B10 amide 65 370 DTP ester B13 eSter 307 PBO ester B10 amide 371 PBO ester B13 eSter US 8,088,935 B2 35 36 TABLE 1-continued TABLE 1-continued

O O O O

Example # R1 linkage R2 linkage Example # R1 linkage R2 linkage

372 - OH na B13 acetal 15 436 B21 amide - OH na 373 - OEt ester B13 acetal 437 B21 amide - OEt ester 374 DTP ester B13 acetal 438 B21 amide DTP ester 375 PBO ester B13 acetal 439 B21 amide PBO ester 376 - OH na B13 amide 440 - OH na B21 amide 377 - OEt ester B13 amide 441 - OEt ester B21 amide 378 DTP ester B13 amide 2O 442 DTP ester B21 amide 379 PBO ester B13 amide 443 PBO ester B21 amide 380 B14 amide - OH na 444 B22 amide - OH na 381 B14 amide - OEt ester 445 B22 amide - OEt ester 382 B14 amide DTP ester 446 B22 amide DTP ester 383 B14 amide PBO ester 447 B22 amide PBO ester 384 - OH na B14 amide 448 - OH na B22 amide 385 - OEt ester B14 amide 25 449 - OEt ester B22 amide 386 DTP ester B14 amide 450 DTP ester B22 amide 387 PBO ester B14 amide 451 PBO ester B22 amide 388 B15 amide - OH na 452 B23 amide - OH na 389 B15 amide - OEt ester 453 B23 amide - OEt ester 390 B15 amide DTP ester 454 B23 amide DTP ester 391 B15 amide PBO ester 30 455 B23 amide PBO ester 392 - OH na B15 amide 456 - OH na B23 amide 393 –OEt ester B15 amide 457 –OEt eSter B23 amide 394 DTP ester B15 amide 458 DTP ester B23 amide 395 PBO ester B15 amide 459 PBO ester B23 amide 396 B16 amide - OH na 460 B24 ester - OH na 397 B16 amide - OEt ester 35 461 B24 ester - OEt ester 398 B16 amide DTP ester 462 B24 ester DTP ester 399 B16 amide PBO ester 463 B24 ester PBO ester 400 - OH na B16 amide 464 - OH na B24 ester 4O1 - OEt ester B16 amide 465 - OEt ester B24 ester 4O2 PF ester B16 amide 466 DTP ester B24 ester 403 BO ester B16 amide 40 467 PBO ester B24 ester 404 B17 amide - OH na 40S B17 amide - OEt ester 4O6 B17 amide DTP ester 407 B17 amide PBO ester 4.08 - OH na B17 amide TABLE 2 409 - OEt ester B17 amide 410 DTP ester B17 amide 45 RI R2 411 PBO ester B17 amide 412 B18 amide - OH na O O 413 B18 amide - OEt ester O O 414 B18 amide DTP ester 415 B18 amide PBO ester 416 - OH na B18 amide 50 417 - OEt ester B18 amide 418 DTP ester B18 amide O O O O 419 PBO ester B18 amide 420 B19 amide - OH na OS 421 B19 amide —OEt ester R3 422 B19 amide DTP ester 55 423 B19 amide PBO ester Example # R1 linkage R2 linkage R3 linkage 424 - OH na B19 amide 425 - OEt ester B19 amide SOO B1 ester –OH nia —H na 426 DTP t B19 d 5O1 B1 ester —OEt ester —H na 427 PBO B19 N. 502 B1 ester DTP ester —H na 428 B2O id - OH f 60 503 B1 ester PBO ester —H na amide li8 SO4 B1 acetal –OH nia —H na 429 B2O amide - OEt ester 505 B1 acetal —OEt ester —H na 430 B2O amide DTP ester SO6 B1 acetal DTP ester —H na 431 B2O amide PBO ester 507 B1 acetal PBO ester —H na 432 - OH na B2O amide SO8 B1 amide –OH nia —H na 433 - OEt ester B2O amide SO9 B1 amide - OEt ester —H na 434 DTP ester B2O amide 65 510 B1 amide DTP ester —H na 435 PBO ester B2O amide 511 B1 amide PBO ester —H na US 8,088,935 B2 37 38 TABLE 2-continued TABLE 2-continued RI R2 RI R2 or O O rs or O O

O I-n- O 10 O 1-n- O On R3 On R3

Example # R1 linkage R2 linkage R3 linkage Example # R1 linkage R2 linkage R3 linkage 512 - OH na - OH na B1 ester 15 576 - OH na - OH nia B5 ester 513 - OEt ester –OH na B1 ester 577 - OEt ester –OH nia B5 ester S14 DTP ester –OH na B1 ester 578 DTP ester –OH nia B5 ester 515 PBO ester –OH na B1 ester 579 PBO ester –OH nia B5 ester S16 - OH na - OH na B1 acetal S8O - OH na - OH nia B5 acetal 517 - OEt ester –OH na B1 acetal 581 - OEt ester –OH nia B5 acetal S18 DTP ester –OH na B1 acetal 2O 582 DTP ester –OH nia B5 acetal 519 PBO ester –OH na B1 acetal 583 PBO ester –OH nia B5 acetal 52O B2 ester –OH nia —H na S84 B6 amide –OH nia —H na 521 B2 ester —OEt ester —H na 585 B6 amide - OEt ester — na 522 B2 ester DTP ester —H na S86 B6 amide DTP ester — na 523 B2 ester PBO ester —H na 587 B6 amide PBO ester — na 524 B2 acetal –OH nia —H na 588 B7 ester –OH nia —H na 525 B2 acetal - OEt ester —H na 25 589 B7 ester —OEt ester — na 526 B2 acetal DTP ester —H na 590 B7 ester DTP ester — na 527 B2 acetal PBO ester —H na 591 B7 ester PBO ester — na 528 B2 amide –OH nia —H na 592 B7 acetal –OH nia —H na 529 B2 amide —OE ester —H na 593 B7 acetal —OEt ester — na 530 B2 amide DTP ester —H na 594 B7 acetal DTP ester — na 531 B2 amide PBO ester —H na 30 595 B7 acetal PBO ester — na 532 - OH na - OH na B2 ester 596 B7 amide –OH nia —H na 533 –OEt ester –OH na. B2 ester 597 B7 amide —OEt ester — na 534 DTP ester –OH na B2 ester 598 B7 amide DTP ester — na 535 PBO ester –OH na B2 ester 599 B7 amide PBO ester — na 536 - OH na - OH na B2 acetal 600 - OH na - OH nia B7 ester 537 - OEt ester –OH na B2 acetal 35 6O1 - OEt ester –OH nia B7 ester 538 DTP ester –OH na B2 acetal 602 DTP ester –OH nia B7 ester 539 PBO ester –OH na B2 acetal 603 PBO ester –OH nia B7 ester S4O B3 ester –OH nia —H na 604 - OH na - OH nia B7 acetal 541 B3 ester —OEt ester —H na 60S - OEt ester –OH nia B7 acetal S42 B3 ester DTP ester —H na 606 DTP ester –OH nia B7 acetal 543 B3 ester PBO ester —H na 40 607 PBO ester –OH nia B7 acetal 544 B3 acetal –OH nia —H na 608 B8 ester –OH nia —H na 545 B3 acetal - OEt ester —H na 609 B8 ester —OEt ester —H na S46 B3 acetal DTP ester —H na 610 B8 ester DTP ester —H na 547 B3 acetal PBO ester —H na 611 B8 ester PBO ester —H na S48 B3 amide –OH nia —H na 612 B8 acetal –OH nia —H na 549 B3 amide —OEt ester —H na 613 B8 acetal —OEt ester —H na 550 B3 amide DTP ester —H n/a 45 614 B8 acetal DTP ester —H na 551 B3 amide PBO ester —H na 615 B8 acetal PBO ester —H na 552 - OH na - OH nia B3 ester 616 B8 amide –OH nia —H na 553 - OEt ester –OH nia B3 ester 617 B8 amide - OEt ester —H na 554 DTP ester –OH nia B3 ester 618 B8 amide DTP ester —H na 555 PBO ester –OH nia B3 ester 619 B8 amide PBO ester —H na SS6 OH na - OH nia B3 acetal 50 620 – OH na - OH nia B8 ester 557 - OEt ester –OH nia B3 acetal 621 - OEt ester –OH nia B8 ester 558 DTP ester –OH nia B3 acetal 622 DTP ester –OH nia B8 ester 559 PBO ester –OH nia B3 acetal 623 PBO ester –OH nia B8 ester S60 B4 amide –OH nia —H na 624 - OH na - OH nia B8 acetal S61 B4 amide —OEt (Sc. - na 625 - OEt ester –OH nia B8 acetal S62 B4 amide DTP (Sc. - na 55 626 DTP ester –OH nia B8 acetal 563 B4 amide PBO (Sc. - na 627 PBO ester –OH nia B8 acetal S64 B5 ester –OH nia —H na 628 B9 ester –OH nia —H na 565 B5 ester —OE (Sc. - na 629 B9 ester —OEt ester —H na 566 B5 ester DTP (Sc. - na 630 B9 ester DTP ester —H na 567 B5 ester PBO (Sc. - na 631 B9 ester PBO ester —H na 568 B5 acetal –OH nia —H na 60 632 B9 acetal –OH nia —H na 569 B5 acetal - OE (Sc. - na 633 B9 acetal —OEt ester —H na 570 B5 acetal DTP (Sc. - na 634 B9 acetal DTP ester —H na 571 B5 acetal PBO (Sc. - na 635 B9 acetal PBO ester —H na 572 B5 amide –OH nia —H na 636 B9 amide –OH nia —H na 573 B5 amide —OE (Sc. - na 637 B9 amide - OEt ester —H na 574 B5 amide DTP (Sc. - n/a 65 638 B9 amide DTP ester —H na 575 B5 amide PBO (Sc. - na 639 B9 amide PBO ester —H na

US 8,088,935 B2

TABLE 2-continued TABLE 2-continued R R2 R1 R2

O O 5 O O or to r

O O O O O O O O 10 O NR3 O NR3 Example # R1 linkage R2 linkage R3 linkage Example # R1 linkage R2 linkage R3 linkage

2. R: eSter 3. estere - : al 15 774 DTP ester –OH n/a B24 acetal 770 B24 ester DTP ester -H na 775 PBO ester –OH n/a B24 acetal 771 B24 ester PBO ester -H na 772 -OH n/a - OH na B24 acetal - - - 773 - OEt ester –OH na B24 acetal Some additional compounds of the invention are shown below to illustrate various further aspects of the invention:

OH O HO

NH O O O O Nur or

O O O O HN )=NH OH NH CH HN= CH3

900 OH HO O O NH O Nun. O O or

HN O 1-n- O

CHX=NH O O HN= NH 3 NH CH3

HN

CH3)=NH 901 US 8,088,935 B2 43 44 -continued

HN)=NH CH 902

CH

903 US 8,088,935 B2 45 46 -continued

)=NH CH3 904

)- CH3 905 US 8,088,935 B2 47 48 -continued

907

908 US 8,088,935 B2 49 50 Example 900 illustrates two iNOS inhibitors attached to a -continued single cromolyn core. In this particular example, both iNOS H inhibitors are the same, but that is not a requirement of the HC N CoH, invention. Similarly, without intending to so restrict the invention, example 901 illustrates three iNOS inhibitors 5 NH F NH 2 H attached to a single cromolyn core. Examples 902-906 illus HC N CoH, trate various mixed esters. Examples 907 and 908 illustrate N-XY acetals of acetaldehyde (whereas the examples in Tables 1 and F F 2 show acetals of formaldehyde); both acetals of acetalde- NH NH2 H hyde and acetals of formaldehyde are within the scope of the 10 CH3 N invention, and each of the formaldehyde acetal examples in r NH2 the tables has a corresponding acetaldehyde acetal example. NH The invention claimed is: F S COOH, 1. A compound of formula I CH3 NH 15 Y F NH2 R I is-N--N COOH, and H H N N COOH: O O H N1 O O 20 2 NH NH2

O O O O —(C=O)R’ is the deshydroxy residue of a carboxylic 25 acid, the parent of which, RCOOH, is chosen from the OS group consisting of: R3 wherein CH3 CO2H, RandR are chosen from hydroxy, C.C.C.C.C.s, and 30 n-n-n C straight and branched alkoxy, -G-O(C=O)R. R. NH NH - NHR,--OR and—OX", wherein X" is a pharma 2 ceutically acceptable cation; CH3 CO2H, R is chosen from hydrogen, —(C=O)R', -(C=O)-G- r N-1Ns O(C=O)R, 7. (C=O)R, (C=O)NHR'' and 35 NH OWV O NH, (C=O)OR'; NH —O(C=O)R’ is the deshydrogen residue of a carboxylic H 2 acid, the parent of which, RCOOH, is chosen from the CH N-1a ~s group consisting of: r S CO2H, 40 NH H CH3 CO2H, CH3 N-1a S ~-lii n-n-n NH NH2 NH NH2 45 H CH3 N N-1\s CO2H, HN

NH NH2 NH2 NH N CHECH COOH, 50 CH3 N- 1-coil. H3C CH3 in-> COH, NH NH NH H 2 CH3 N CO2H, H n-n-n 55 " --~~" NH NH2 NH F NH2 H H3C N COH, HN 60 NH N F F CHECH COOH, NH NH2 H H CH CH N H3C N NH2 COH, 65 NH NH NH2 1s COOH,

US 8,088,935 B2 53 54 OR7 is -continued H HC N CO2H O N-XY /SS H O X : 5 NH F F NH2 Yu-N n N O CH

N 2 NH O 1s COOH NH olo 10 "se F NH 2

G is chosen from —OCH and —OCH(CH)–: I-N-- and at least one of R, R and R must be -G-O(C=O)R, H H

R" is chosen from C to C alkyl, Cs to C cycloalkyl, C, NH NH2 to Ca hydroxyalkyl and C to Chaloalkyl; Q is chosen from CH-CH=CHCH , -(CH2).X (CH2). , —O , NRI and (CH), A(CH.) : 20 3. A compound according to claim 1 wherein RCOOH and p is 2 or 3: RNH are chosen from compounds of structure: q is 1 or 2; X is S(O), X is 0, 1 or 2; R50 5 ity C- alkyl, 25 HC Nulls, CO2H S is 1 or 2; and r ~ A is cyclobutyl, phenyl or pyridyl. NH NH2 2. A compound according to claim 1 wherein RCOOH and RNH2 are chosen from: 30 wherein R is chosen from C to C alkyl, C. to C. cycloalkyl, C to Ca hydroxyalkyl and C to Ca haloalkyl. 4. A compound according to claim 1 wherein RCOOH and H3C NH2 3s RNH are chosen from compounds of structure:

NH H COH CH3 N-- 40 HC r N-Q ( NH2 NH NH2 NH H CH3 N N-1\s CO2H / \, wherein Q is chosen from —CH-CH=CHCH , NH N. 45 -(CH2)x(CH) , -O-, -NR'— and H ~s —(CH2), A(CH2) ; CH3 N N-1 ns CO2H p is 24 or 3:; q is 1 or 2; N H 50 X is S(O); CH3 N- CO2H X is 0, 1 or 2; ~. R" is H or C. alkyl: NH NH2 r is 1 or 2;

55 S is 1 or 2; and HN A is cyclobutyl, phenyl or pyridyl. NH N -- 5. A compound according to claim 1 wherein R'NH is CHCH COOH chosen from compounds of structure: H CH3 HC N n-n-N- CO2H 60 CH3 NH NH2 H H

"---~~ 65 2 CII . . . 2 NH F NH2 N NH2 N NH2 US 8,088,935 B2 55 56 -continued 10. A compound according to claim 1 of formula HN N n NH RI R2 N 2 2N 5 O O S. S CH NH2 O O NH NH ls CH NH2 HN s1 HN N1 10 HC N O 1--> O

NH s )-Ni, Ne R4 NH2 15 HN ls s1\-1 CH st N wherein O HN e V RandR are chosen from hydroxy, C.C.C.C.C.s, and H N HC N N / C straight and branched alkoxy and—OX". N N 2O 11. A compound according to claim 1 of formula: H NH NH2 R5 R5

H O O "> NH2 25 O O. NH NH 21 H H N N N CH3. 30 / N (CH2)4 O i-n- O N O \ NH O HN NY R4 6. A compound according to claim 1 wherein 35 12. A compound according to claim 1 of formula: RandR are chosen from hydroxy, C.C.C.C.C.s, and Castraight and branched alkoxy, R. NHR'. —OR and —OX"; and RI R2 R is chosen from hydrogen, —(C=O)R. (C=O)R. O O (C=O)NHR'' and (C=O)OR7. 40 O O 7. A compound according to claim 1 wherein at least one of 21 G is chosen from —OCH and —OCH(CH)—. 45 O 1--> O 8. A compound according to claim 1 wherein R is OH

wherein 50 R" is chosen from-G-O(C=O)R, NHR and OR7; and R is chosen from hydroxy, C, C, C, C, Cs, and C. -o-c-( ) straight and branched alkoxy, Rand—OX. 13. A pharmaceutical composition comprising a pharma ceutically acceptable carrier and a compound according to 9. A compound according to claim 1 wherein R is 55 claim 1. 14. An aerosol pharmaceutical composition according to claim 13. S 15. An oral pharmaceutical composition according to O N claim 13. 16. An oral pharmaceutical composition according to r 60 claim 15 in the form of a tablet, capsule or syrup.

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