US 2017.0056379A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0056379 A1 Chen et al. (43) Pub. Date: Mar. 2, 2017

(54) METHOD OF USING ation of application No. 13/509,881, filed on Sep. 24, REUPTAKE INHIBITORS AND THEIR 2012, now Pat. No. 9,119,843, filed as application No. ANALOGS FOR TREATING DABETES PCT/US2010/058864 on Dec. 3, 2010. SYMPTOMIS AND DELAYING OR PREVENTING DABETES-ASSOCATED (60) Provisional application No. 61/266,740, filed on Dec. PATHOLOGIC CONDITIONS 4, 2009. (71) Applicant: CALIPER LIFE SCIENCES, INC., Hopkinton, MA (US) Publication Classification (72) Inventors: Hao Chen, Columbia, MD (US); Ming (51) Int. Cl. Liu, Rockville, MD (US); Malathi A6II 3/42.45 (2006.01) Sathyamoorthy, Ellicott City, MD A6II 45/06 (2006.01) (US); Qi Su, Columbia, MD (US); Lisa (52) U.S. Cl. Leary, Edgewater, MD (US); Wayne CPC ...... A61K 31/4245 (2013.01); A61K 45/06 Shaobin Zhong, Gaithersburg, MD (2013.01) (US) (21) Appl. No.: 15/350,221 (57) ABSTRACT (22) Filed: Nov. 14, 2016 Method of using dopamine reuptake inhibitors, e.g., Syd Related U.S. Application Data nonimine derivatives, for the management of diabetic symp (63) Continuation of application No. 14/841,664, filed on toms and associated complications or conditions, such as Aug. 31, 2015, now abandoned, which is a continu hyperglycemia and diabetic neuropathy. Patent Application Publication Mar. 2, 2017 Sheet 1 of 2 US 2017/0056379 A1

18O

160 i OO 1 OO

8O high fat D high fat N normal D normal N. With Control Mice Dunnett's O.05

Fig. 1

26O

240 1228O2 OOO | 16 O 140

12O high fat D high fat N normal D normal N. With Control Mice Dunnett's O.05

Fig. 2 Patent Application Publication Mar. 2, 2017 Sheet 2 of 2 US 2017/0056379 A1

6O

40 4N Z Y 3O 2O t/ Y/ S high fat D high fat N normal D normal N Nantga Mice

Fig. 3

high fat D high fat N normal D normal N With Control Mice Dunnett's O.05 Fig. 4 US 2017/0056379 A1 Mar. 2, 2017

METHOD OF USING DOPAMINE 0007 Diabetic conditions are often linked with altered REUPTAKE INHIBITORS AND THEIR central and sympathetic nervous systems. Most chronic ANALOGS FOR TREATING DABETES diabetic patients eventually develop neuropathy of different SYMPTOMIS AND DELAYING OR clinical manifestations. According to a statement made by PREVENTING DABETES-ASSOCATED the American Diabetes Association, the most common PATHOLOGIC CONDITIONS among the neuropathies are chronic sensorimotor distal symmetric polyneuropathy (DPN) and the autonomic neu CROSS-REFERENCE TO RELATED ropathies. Up to 50% of DPN may be asymptomatic but the APPLICATIONS patient is at risk of insensate injury to their feet and >80% of amputations follow a foot ulcer or injury. Additionally, 0001. The present application is a continuation of U.S. Such neuropathy also includes autonomic manifestations of patent application Ser. No. 14/841,664, filed Aug. 31, 2015, every system in the body, which causes substantial morbid which is a continuation of U.S. patent application Ser. No. ity and increased mortality, particularly when cardiovascular 13/509,881, filed Sep. 24, 2012, which is a U.S. National autonomic neuropathy (CAN) is present. Glucose and/or Stage of International Patent Application No. PCT/US2010/ insulin are not known to directly mediate sensory or noci 058864, filed Dec. 3, 2010, which claims the benefit of U.S. ceptive perceptions such as hypoalgesia or hyperalgesia Provisional Patent Application No. 61/266,740, filed Dec. 4, (different neuropathic manifestations), nor are they known 2009, the entire disclosures of which are incorporated by to be linked with cardiovascular autonomic regulations. reference herein. Literature reports indicate that strict glycemic control may mediate neuropathies, but not eliminate the symptoms FIELD OF INVENTION entirely. These indications point to other neurological 0002 The present invention relates to the field of phar mediators that 1) contribute to the regulation of glucose/ macological management of diabetes and various associated energy homeostasis and 2) are dis-regulated under pre disease manifestations. More specifically, the present inven diabetic or diabetic conditions (genetic and/or environmen tion provides a method of using dopamine reuptake inhibi tal factors). tors, including certain Sydnonimine derivatives, for the 0008 Epidemiological studies have linked child-hood management of diabetic symptoms and associated compli obesity and diabetes with neurological dysfunctions like cations or conditions, such as hyperglycemia and diabetic attention deficit hyperactive disorder (ADHD). These stud neuropathy. ies suggest that dopaminergic transmission that evolved to increase cognition is also coupled with attention and energy BACKGROUND OF THE INVENTION management (Campbell and Eisenberg, 2007). One of the working hypotheses regarding ADHD etiology is that 0003 Diabetes is a modern epidemic affecting an increas patients have handicapped energetic management between ingly large number of populations from industrial countries neuronal and glial cells (Russell, et al 2006). Besides to the developing world. The cost of managing diabetes in ADHD, there is a substantial body of clinical evidence and the United States alone is about S174 billion, S116 billion of research reports linking anxiety, stress and depression with which are directed towards medical care. diabetes. These mechanisms are still to be explored and 0004. The hallmark symptom of diabetes mellitus is understood. Nevertheless, the response of neuroendocrine, hyperglycemia, i.e. high levels of blood glucose (also known hypothalamic-pituitary-adrenal axis and sympathetic ner as blood Sugar). Such conditions are primarily the result of Vous system, to stressors may be key contributing factors to insufficient insulin production (Type I diabetes) or from the underlying etiology. Based on these studies, a panel of defects in response to insulin action (Type II diabetes). A experts has suggested that activation of the dopaminergic chronic diabetic condition causes serious complications or circuitry may be a viable and effective clinical management co-morbidities, such as heart disease, stroke, impaired renal paradigm (Blum et al., 2008). function, or nephropathy, high blood pressure, both central 0009 Diabetes alters the central and sympathetic nervous and peripheral nerve damage or neuropathy, cataracts and/or systems that may lead to behavior manifestations. Stress and blindness and amputations. depression, central nervous system conditions, may cause 0005 According to the National Diabetes Information metabolic changes leading to diabetes. These disease symp Clearinghouse (NDIC) report (a service provided by toms may share common roots. To further support the role National Institute of Diabetes and Digestive and Kidney of neuronendocrine system in diabetes, especially with Diseases, NIDDK, NIH), in the United States, in 2007 there regards to the role of dopaminergic function, there is a were 23.6 million (approximately 7.8 percent of the popu Substantial body of Supporting evidence from animal studies lation) diabetic patients along with 1.6 million new cases of When treated neonatally with monosodium glutamate, Wis diabetes diagnosed in the same year. About half (12.1 tar rats develop symptoms of Type II diabetes, i.e. hyper million) of the diabetic population is age 60 or older. glycemia, glucose intolerance, beta-cell morphological Moreover, an estimated 57 million American adults exhibit changes, and sensory and autonomic nerve changes includ pre-diabetic conditions (e.g. persistent hyperglycemic con ing the development of a hypoalgesic state. Concomitantly, ditions) in 2007, a warning sign of potential outbreak. there are noted changes in catecholamine synthesis in dif 0006. The etiology of diabetes is still under investigation. ferent peripheral tissues and sympathetic nerves (Morrison The primary focus of diabetic management is the reduction et al., 2007). of blood glucose levels. Few therapeutic initiatives with 0010. In one animal model of Type I diabetes (Sprague regard to diabetic management started with a neurological Dawley rats treated with Streptozotocin), a brief episode of approach. Mediating and attenuating diabetic neurological the chemically induced diabetes brought changes in dop symptoms are often afterthoughts. aminergic neurotransmission by reducing levels of dop US 2017/0056379 A1 Mar. 2, 2017 amine in a tissue specific manner. Notably, in the peripheral (glyburide). Metformin inhibits the release of glucose from (sympathetic) nervous system, dopamine content remains liver glycogen; Glibenclamide (and other Sulfonylureas), unperturbed at adrenal glands, blood serum and cardiac inhibits pancreatic beta-cell potassium channels, and thus ventricles; yet there is a 14 to 15 fold reduction of dopamine stimulates insulin secretion. Although these drugs are mostly in the stellate ganglion (physiologically, the human Stellate safe, they cannot be used in patients with compromised ganglion, or cervicothoracic ganglion, may be blocked for hepatic functions. There are other drugs that mediate the different medical conditions; reduction of catecholamine diabetic condition by alternative biochemical mechanisms, may be an indication of the reduction of catecholamine e.g. Stimulating insulin secretion (e.g. repaglinide), inhibit neurotransmission in the sympathetic nerves system leading ing glucose (e.g. glucosidase inhibitor, acar to conditions such as DPN). In the central nervous system, bose), mediating gastric emptying (e.g. pramlintide), etc. dopamine levels remain unchanged at medulla and pons; The most recent diabetic are of gluca however, there is a 4-fold reduction in the midbrain and a gon-like peptide-1 of the incretin hormone receptor (GLP-1 5-fold reduction in the striatum (an underlying biochemical ) and dipeptidyl-peptidase-4 inhibitors (e.g. Sitaglip mechanism of neurological manifestations and symptoms, tin). A common complication of most of these drugs is Such as ADD, depression, anxiety and Parkinson's disease). hypoglycemia, a condition often resulting in seizures, Changes in other catecholamines, e.g. and unconsciousness and occasionally permanent brain damage epinephrine, are noted but less significant (Gallego et al. or death. Ideally, a pharmacological agent capable of main 2003). In another study, besides similar observations in taining glucose homeostasis at a healthy level without Such altering catecholamine levels in different brain regions, short complications would improve the current diabetes treatment term diabetes also altered the expression levels of signal paradigm. transduction proteins such as CaMKII. PKC-alpha, and 0015 The human clinical evidence, human epidemio p38-MAPK kinases, indicating the impact of diabetes at the logical and animal model Studies referred to above Support neuronal level (Ramakrishnan et al., 2005) and changes in the concept that activation of the dopaminergic circuitry cellular signal transductions. may be a viable and effective clinical management approach 0011 Human epidemiological studies have shown that for both Type I and Type II diabetes. when humans are on a limited caloric diet, there are fewer incidences of diabetes, as well as cancer, obesity, anxiety, SUMMARY OF THE INVENTION depression and many other disease states and conditions. When the BL/6 is on a healthy and constant caloric restric 0016 To address the need of developing more effective tion diet (recapitulating human condition), the animal Sub ways of treating diabetic symptoms and managing condi jects show less anxiety and less depressive behavior, that is tions associated with diabetes, and diabetic neuropathy in the caloric-restricted (CR) subjects spend more time in the particular, the present invention provides a method employ center of the open field study; more time in the open arm of ing one or more dopamine reuptake inhibitors that may be the elevated plus maze study, and less time immobilized in used for the treatment of diabetic symptoms and/or prophy the forced Swim test (as compared with binge fed and normal laxis of diabetes-associated pathologic conditions. control models). Dopaminergic and alpha-adrenergic signal transduction are amongst the top up-regulated genes (poten 0017 Such dopamine reuptake inhibitors may be admin tially indicating the underlying mechanism between ADHD istered individually, or in combination, as well as in a and diabetes) in these CR subjects. And the western blot combination including at least one other active agent that is analysis indicated a specific activation of dopaminergic effective in diabetes management. activities (e.g. up-regulation of cAMP-regulated phosphop 0018 Based on studies conducted to date by the present rotein, a protein specifically associated with dopaminergic inventors, it appears that the method of the invention may be neurotransmissions). effective to attenuate diabetic neurological manifestations 0012. From the above discussions, it may be concluded Such as neuropathic pain, sensorimotor distal symmetric that 1) the diabetic condition appears to negatively impact polyneuropathy and autonomic neuropathy. As a result, the the catecholaminergic, especially dopaminergic systems method of the invention may also be effective for restoring leading to conditions of neuropathology; and/or 2) neuro sensation in lower extremities. pathological conditions may negatively impact the “insulin 0019. Thus, the present invention offers a holistic ergic” system, thus Supporting the diabetic condition. There approach to diabetes management by Supplementing glyce is increasing evidence in the literature indicating the impor mic control with mediating and attenuating neurological tance of insulin in neurological functions, including age symptoms using the methods described herein. As will related neurodegenerative conditions such as Alzheimer's appear below, this improved treatment modality is based on disease. a greater understanding of related patho-biochemical 0013 There is currently no cure for either Type I or Type mechanisms, including neurobiology, provided by the pres II diabetes. Life style changes, e.g. changing diet and ent inventors. increasing exercise, may mediate aspects of disease-related conditions, but such changes and alternatives are often DESCRIPTION OF DRAWINGS AND TABLES neither feasible nor effectively adopted, especially in aging populations. Pharmacological management is the primary 0020 FIG. 1. A graphical representation demonstrating means to control the development of diabetic complications. that after seven weeks, mice fed on high fat diet showed 0014 For Type I diabetes, the management has been with robust hyperglycemic condition. insulin. Pharmacological intervention of Type II diabetes has 0021 FIG. 2. A graphical representation demonstrating been attempted with blood glucose control using medica that after 4 weeks of treatment with a dopamine reuptake tions such as Metformin (glucophage) or Glibenclamide inhibitor, the blood glucose levels of the dopamine reuptake US 2017/0056379 A1 Mar. 2, 2017 inhibitor (3-(phenylpropyl)-sydnonimine-N-phenylcarbam 0029. It should be appreciated that compounds of For oyl) treated mice became indistinguishable from the group mula (I), above, may have one or more asymmetric centers of mice fed a Normal Diet. and thus exist as stereoisomers, including enantiomers and 0022 FIG. 3. A graphical representation demonstrating diastereomers, which are usually named according to the that a dopamine attenuated the hypoalge Cahn-Ingold-Prelog system. Although the structure of For sic (an indication that recapitulates the human condition of mula I is represented without regard to stereochemistry, it is DPN) conditions induced by diabetic conditions (hot plate intended to include all possible stereoisomers, which may be test). racemic mixtures or other mixtures of Rand Sistereoisomers 0023 FIG. 4. A graphical representation demonstrating (scalemic mixtures which are mixtures of unequal amounts that a dopamine reuptake inhibitor attenuated the hypoalge of enantiomers), as well as resolved, Substantially pure sic (an indication that recapitulates the human condition of optically active forms, and pharmaceutically acceptable salts DPN) conditions induced by diabetic conditions (tail-flick thereof. test). 0030 Stereoisomers of the compounds of Formula (I), above, can be selectively synthesized or separated into pure, DETAILED DESCRIPTION OF THE optically-active form using conventional procedures known INVENTION to those skilled in the art of organic synthesis. For example, 0024. Among the dopamine reuptake inhibitors that may mixtures of stereoisomers may be separated by standard be used in practicing this invention are compounds of the techniques including, but not limited to, resolution of race formula: mic forms, normal, reverse-phase, and chiral chromatogra

(I) O Rs

R k * NN-1 () R R2

0025 wherein R. R. R. R. Rs and R, independently phy, preferential salt formation, recrystallization, and the of one another, are substituents selected from H. C-C, like, or by chiral synthesis either from chiral starting mate alkyl, OH, halogen, Cs-C aryl, C-C aralkyl, C-C, rials or by deliberate synthesis of target chiral centers. alkylthio, C-C alkoxy, SH, C-C alkenyl, C-C alkynyl, 0031 All of the various isomeric forms of the compound C-C cycloalkyl, CN, NO, carboxy, carbalkoxy, carbox of Formula (I), above, are within the scope of this invention. amido, alkylsulfonyl, alkylsulfonyloxy, aminosulfinyl, 0032. As used herein, the “alkyl refers to saturated monoalkylaminosulfinyl, dialkylaminosulfinyl, aminosulfo straight and branched chain hydrocarbon radicals, having nyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkyl 1-6 and preferably 1-4 carbon atoms. The term “alkenyl is Sulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, used to refer to unsaturated Straight and branched chain alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkyl hydrocarbon radicals including at least one double bond, and Sulfonylalkyl, aminosulfonylalkyl, monoalkylaminosulfo having 2-7 and preferably 2-5 carbon atoms. Such alkenyl nylalkyl, dialkyaminosulfonylalkyl, aminosulfinylalkyl, radicals may be in trans (E) or cis (Z) structural configura monoalkylaminosulfinylalkyl, dialkylaminosulfinylalkyl, tions. The term “alkynyl is used herein to refer to both said alkyl, alkenyl, alkynyl or cycloalkyl Substituent being straight and branched unsaturated hydrocarbon radicals optionally substituted by at least one halogen, OH, SH, NH, including at least one triple bond and having 2-7 and C-C monoalkylamino, C-C dialkylamino, COOH, CN, preferably 2-5 carbon atoms. NO, C-C alkyl or C-C alkoxy group, said aryl and aralkyl substituent being optionally substituted by at least 0033. The term “cycloalkyl as used herein refers to a one halogen, OH, SH, NH, C-C monoalkylamino, C-C, saturated cyclic hydrocarbon radical with one or more rings, dialkylamino, COOH, CN, NO, C-C alkyl or C-C, having 3-14 and preferably 5 or 6-10 carbon ring-atoms. alkoxy group: 0034. Any alkyl, alkenyl, alkynyl or cycloalkyl moiety of 0026 R. R., and R, independently of one another, rep a compound described herein may be substituted with one or resent substituents selected from H. C-C alkyl, phenyl or more groups, such as halogen, OH, SH, NH, C1-C4 mono phenyl C-C alkyl, said alkyl Substituent, said phenyl Sub alkylamino, C1-C4 dialkylamino, COOH, CN, NO2, C1-C4 stituent and said phenyl C-C alkyl Substituent being alkyl or C1-C4 alkoxy. optionally substituted by at least one halogen, OH, SH, NH, 0035. The term “aryl' as used herein refers to an aromatic C-C methylalkylamino, C-C dialkylamino, COOH, CN, hydrocarbon radical composed of one or more rings and NO, C-C alkyl or C-C alkoxy group; having 5 or 6-14 carbon atoms and preferably 5 or 6-10 carbon atoms, such as phenyl, naphtnyl, biphenyl, fluorenyl, 0027 m, n and k are independent integers from 0-4, indanyl, or the like. Any aryl moiety of a compound except that m+nz0; described herein may be substituted with one or more 0028 and the pharmaceutically acceptable salts of said groups, such as halogen, OH, SH, NH2, C1-C4 monoalky compound. lamino, C1-C4 dialkylamino, COOH, CN, NO2, C1-C4 US 2017/0056379 A1 Mar. 2, 2017 alkyl or C1-C4 alkoxy. The aryl moiety is preferably sub compounds in which the A ring is para-Substituted, e.g., stituted or unsubstituted phenyl. 3-(p-methylbenzyl)Sydnominine-N-phenylcarbamoyl, com 0036. The term “arylalkyl or “aralkyl as used herein pounds in which the B ring is 3,4-di-Substituted, e.g., refers to radicals having 6 to 20 carbon atoms that combine 3-phenethyl-sydnominine-N-(3',4'-dichlorophenyl)carbam both an aryl and an alkyl group, as defined above. Any oyl and compounds in which the A ring is para-Substituted aralkyl moiety of a compound described herein may option and the B ring is 3,4-di-Substituted, e.g., 3-(p-nitrophen ally be substituted with one or more of the same substituent ethyl)-sydnominine-N-(3',4'-dinitro-phenyl)carbamoyl. groups mentioned above in reference to the aryl radical. Also preferred are compounds wherein m+n=1 or 3 in 0037. The term “halogen” or “halo' as used herein refers formula (I), above. to F1, Cl, Brand I. 0057 The term “pharmaceutically acceptable salts' as 0038. The term “alkoxy” refers to alkyl-O-, in which used herein refers to salts derived from non-toxic physi alkyl is as defined above. ologically compatible acids and bases, which may be either 0039. The term “alkylthio” refers to alkyl-S in which inorganic or organic. Thus, when a compound of Formula I alkyl is as defined above. has an acid moiety, e.g., 3-(p-carboxybenzyl), Sydnominine 0040. The term “carboxy” refers to the moiety - C(=O) N-phenylcarbamoyl, useful salts may be formed from physi OH. ologically compatible organic and inorganic bases, includ 0041. The term “carbalkoxy” refers to the moiety ing, without limitation, alkali and alkaline earth metal salts, —C(=O)C-alkyl, in which alkyl is as defined above. e.g., Na, Li, K, Ca, Mg, as well as ammonium salts, and salts 0042. The term “carboxamido” refers to the moiety of organic amines, e.g., ammonium, trimethylammonium, —C(=O)C) NR'R", in which R" and R", each indepen diethylammonium, and tris-(hydroxymethyl) methylammo dently represents H, alkyl, aryl or aralkyl, all as previously nium salts. The compounds of the invention also form salts defined. with organic and inorganic acids, including, without limita 0043. The term “alkylsulfonyl refers to the moiety tion, acetic, ascorbic, lactic, citric, tartaric, succinic, —S(=O)-alkyl, in which alkyl is as previously defined. fumaric, maleic, malonic, mandelic, malic, phthalic, salicy 0044) The term “alkylsulfonyloxy' refers to the moiety clic, hydrochloric, hydrobromic, phosphoric, nitric, Sulfuric, —OS(=O)-alkyl, wherein alkyl is as previously defined. methane Sulfonic, naphthalene Sulfonic, benzene Sulfonic, 0045. The term “amino(monoalkylamino-, dialky toluene Sulfonic and similar known, physiologically com lamino-)sulfinyl refers to the moiety - S(=O)NR'R" in patible acids. In addition, when a compound of Formula I which R' and R" each independently represents H, alkyl, aryl contains both a basic moiety and an acidic moiety, Zwitte or aralkyl, all as previously defined. rions (“inner salts') may be formed and are included within 0046. The term “amino(monoalkylamino-, dialky the term "salt(s) as used herein. lamino-)sulfonyl refers to the moiety —S(=O)NR'R", in 0058. In general, the compounds of the invention can be which R" and R" each independently represents H, alkyl, aryl administered to achieve specific dopamine reuptake inhibi or aralkyl, all as previously defined. tion by using any acceptable means known in the art, either 0047. The term “alkylsulfonylamino” refers to the moiety alone or in combination with one or more other therapeutic —NHS(=O)-alkyl, in which alkyl is as previously defined. agents. Thus, the active agent(s) can be administered orally, 0048. The term “hydroxysulfonyloxy' refers to the moi parenterally, Such as by intravenous or intraarterial infusion, ety —OS(=O).OH. intramuscular, intraperitoneal, intrathecal or Subcutaneous 0049. The term “alkoxysulfonyloxy” refers to the moiety injection, by liposome-mediated delivery, rectally, vaginally, —OS(=O).O-alkyl, in which alkyl is as previously defined. by inhalation or insufflation, transdermally or by otic deliv 0050. The term “alkylsulfonyloxy” refers to the moiety ery. —OS(=O)-alkyl, in which alkyl is as previously defined. 0059. The method of treating diabetic symptoms and 0051. The term “hydroxysulfonyl refers to the moiety delaying or preventing diabetes-associated pathologic con —S(=O).OH. ditions described herein may be used as an adjunct to the 0052. The term “alkoxysulfonyl refers to the moiety current standard of care for both Type I and Type II diabetes. —S(=O)C-alkyl, wherein alkyl is as previously defined. To that end, one or more of the dopamine reuptake inhibitors 0053. The term “alkylsulfonylalkyl refers to the moiety described herein may be coadministered with insulin, for the -alkyl-S(=O)-alkyl, wherein alkyl (each instance) is as treatment of Type I diabetes, or with any of the numerous previously defined. agents administered for the treatment of Type II diabetes. 0054 The term “amino(monoalkylamino-, dialky The latter include, without limitation, glucophage, gly lamino-)sulfonylalkyl refers to the moieties -alkyl-S(=O) buride, repaglinide, acarbose, pramlintide and Sitagliptin. NR'R", wherein alkyl is as previously defined, and R' and These agents may be administered as separate dosage units R" each independently represents H, alkyl, aryl or aralkyl, or formulated for administration together, according to pro all as previously defined. cedures well known to those skilled in the art. See, for 0055. The term “amino(monoalkylamino-, dialky example, Remington. The Science and Practice of Phar lamino-)sulfinylalkyl refer to the moieties -alkyl-S(=O)— macy, 20" ed., A. Genaro et al., Lippencot, Williams & NRR", wherein alkyl is as previously defined, and R' and R" Wilkins, Baltimore, Md. (2000). each independently represents H, alkyl, aryl or aralkyl, all as 0060. The dopamine reuptake inhibitors described above previously defined. may be administered singly or together, as well as in 0056 Preferred are the compounds of Formula (I), above, combination (singly or together) with at least one dopamine wherein phenyl rings A and/or B are mono- or di-substituted. receptor agonist. The dopamine receptor agonists that may When the A and/or B ring is mono-substituted, para-substi be used in accordance with the present invention includes, tution is preferred. When the A and/or B ring is di-substi without limitation, cabergoline, pergolide, pramipexole, tuted, 3.4 di-substitution is preferred. Most preferred are ropinirole, apomorphine, rotigotine, fenoldopam, dopamine, US 2017/0056379 A1 Mar. 2, 2017

and levodopa. These are clinically effective dopamine recep 0069. As used herein, the expression “a method for tor agonists, which should be administered in accordance treatment of diabetic symptoms’ refers to a treatment using with the manufacturers’ recommendations. one or more of the dopamine reuptake inhibitors described 0061 The dopamine reuptake inhibitors described above herein, with or without the aforementioned MAOIs and may be administered singly or together, as well as in COMTIs, which provide relief oralleviation of the clinically combination (singly or together) with at least one of a recognized symptoms of diabetes including, without limita inhibitor (MAOI) and a catecholamine tion, hyperglycemia. The methods described herein may also o-methyl transferase inhibitor (COMTI). be used to delay the onset or prevent the occurrence of 0062. A MAOI, when used in the practice of this inven diabetes-associated pathologic conditions. The more com tion, has the effect of promoting dopaminergic functions by mon types of diabetic complications are diabetic sensory inhibiting dopamine metabolism, thus extending and expand neuropathy, diabetic autonomic neuropathy, diabetic neph the duration and functional domain of dopaminergic activi ropathy, diabetic retinopathy, and diabetic angiopathy. ties. 0070 The compounds of the invention will typically be 0063 Suitable MAOIs include, without limitation, administered from 1-4 times a day, so as to deliver the , , , Harmalol, Ben above-mentioned daily dosage. However, the exact regimen moxin (Nerusil, Neuralex), (Apresoline) for administration of the compounds and compositions , (Sursum), (Marsilid, described herein will necessarily be dependent on the needs Iprozid, Ipronid, Rivivol, Propilniazida), of the individual subject being treated, the type of treatment (Marplan), Mebanazine (Actomol), Metfendrazine (H.M.- administered and the judgment of the attending medical 11), , (Niamid), Phenel specialist. As used herein, the term “subject' includes both zine (Nardil), (Catron), humans and animals. (Drazine), Pivalylbenzhydrazine (Ter 0071. The compounds of the invention may be adminis savid, Neomarsilid), (Safra). Non-, Tra tered as such, or in a form from which the active agent can nylcypromine (Parnate). , (Conso be derived, such as a prodrug. A prodrug is a derivative of nar), , Clorgyline, Curcumin, , a compound described herein, the pharmacologic action of (Cantor), (Aurorix, Manerix), which results from the conversion by chemical or metabolic (Pirazidol), (Humoryl), Tyrima processes in vivo to the active compound. Prodrugs include, (CX157), Desmethoxyyangonin, Epicatechin, without limitation, ester derivatives of the compounds of , (Eutonyl), Piperine, (AZi formula I, above. Other prodrugs may be prepared according lect), . to procedures well known in the field of medicinal chemistry and pharmaceutical formulation Science. See, e.g., Lombaert 0064 COMTI may be used in carrying out the method of et al., J. Med. Chem., 37: 498-511 (1994); and Vepsalainen, the invention, in order to inhibit dopamine metabolism, thus Tet. Letters, 40: 8491-8493 (1999). extending and expanding the duration and functional domain 0072 The orally administered dosage unit may be in the of dopaminergic activities. form of tablets, caplets, dragees, pills, semisolids, Soft or 0065 Suitable COMTI for this purpose include, without hard gelatin capsules, aqueous or oily Solutions, emulsions, limitation, and . Suspensions or syrups. Suitable dosage forms for parenteral 0066. The above-described MAOI and COMTI are clini administration include injectable solutions or Suspensions, cally useful therapeutic agents which should be administered Suppositories, powder formulations. Such as microcrystals or in accordance with the manufacturers’ recommendation. aerosol spray. The active agent may also be incorporated 0067. Each of the aforementioned therapeutic agents, i.e., into a conventional transdermal delivery system. dopamine reuptake inhibitor(s), MAOI(s) and COMTI(s) 0073. As used herein, the expression “pharmaceutically may be co-administered in the form of discrete dosage units, acceptable carrier medium' includes any and all solvents, or formulated for administration together, using procedures diluents, or other liquid vehicle, dispersion or Suspension described in Remington. The Science and Practice of Phar aids, Surface agent agents, isotonic agents, thickening or macy, Supra. emulsifying agents, preservatives, Solid binders, lubricants, 0068 Normally, a daily dose of the compound of the fillers and the like as suited for the particular dosage form invention in the range from about 0.01 mg to about 200 desired. Remington: The Science and Practice of Pharmacy, mg/kg of body weight can be administered. A daily dose of 20" edition, A. R. Genaro et al., Part 5, Pharmaceutical from 0.1 to 100, and preferably from 1 to 30 mg/kg per day Manufacturing, pp. 669-1015 (Lippincott Williams & in one or more applications per day should be effective to Wilkins, Baltimore, Md./Philadelphia, Pa.) (2000)) discloses produce the desired result. By way of example, a suitable various carriers used in formulating pharmaceutical compo dose for oral administration would be in the range of 1-30 sitions and known techniques for the preparation thereof. mg/kg of body weight per day, whereas a typical dose for Except insofar as any conventional pharmaceutical carrier intravenous administration would be in the range of 1-10 medium is incompatible with the compounds of the present mg/kg of body weight per day. Of course, as those skilled in invention, such as by producing an undesirable biological the art will appreciate, the dosage actually administered will effect or otherwise interacting in an deleterious manner with depend upon the condition being treated, the age, health and any other component(s) of a formulation comprising Such weight of the recipient, the type of concurrent treatment, if compounds, its use is contemplated to be within the scope of any, and the frequency of treatment. Moreover, the effective this invention. dosage amount may be determined by one skilled in the art 0074 For the production of solid dosage forms, including on the basis of routine empirical activity testing to measure hard and soft capsules, the therapeutic agent may be mixed the bioactivity of the compound(s) in a bioassay, and thus with pharmaceutically inert, inorganic or organic excipients, establish the appropriate dosage to be administered. Such as lactose. Sucrose, glucose, gelatine, malt, silica gel, US 2017/0056379 A1 Mar. 2, 2017

starch or derivatives thereof, talc, Stearic acid or its salts, prophylactic effect brought about in the patient undergoing dried skim milk, Vegetable, petroleum, animal or synthetic treatment with the compound(s) and/or composition(s) oils, wax, fat, polyols, and the like. For the production of described herein. liquid Solutions, emulsions or Suspensions or syrups one 0080. The studies described below indicate that enhanced may use excipients such as water, alcohols, aqueous Saline, central and/or sympathetic dopaminergic activity resulting aqueous dextrose, polyols, glycerine, lipids, phospholipids, from inhibiting dopamine reuptake will mediate conditions cyclodextrins, vegetable, petroleum, animal or synthetic associated with diabetes. oils. For Suppositories one may use excipients, such as I0081. While not wishing to be confined to any particular vegetable, petroleum, animal or synthetic oils, wax, fat and theory as to the mechanism of action of dopamine reuptake polyols. For aerosol formulations, one may use compressed inhibitors in treating diabetes symptoms and delaying or gases Suitable for this purpose. Such as oxygen, nitrogen and preventing diabetes-associated pathologic conditions, as carbon dioxide. The pharmaceutical composition or formu described herein, it is believed that the observed attenuation lation may also contain one or more additives including, of diabetic manifestations is due to enhancements of dop without limitation, preservatives, stabilizers, e.g., UV stabi aminergic transmissions. lizers, emulsifiers, Sweeteners, salts to adjust the osmotic I0082. After releasing dopamine into the synaptic cleft, pressure, buffers, coating materials and antioxidants. the neurotransmitter extracellular concentration is regulated 0075. The present invention further provides controlled by the reuptake protein (DAT) and by diffusion. A reuptake release, Sustained-release, or extended-release therapeutic inhibitor will block dopamine reuptake, consequently dosage forms for the pharmaceutical composition, in which extending the neurotransmitter interaction with its receptors the composition is incorporated into a delivery system. This and expanding the domain of dopaminergic ligand-receptor dosage form controls release of the active agent(s) in Such a interaction. That is, dopamine reuptake inhibition enhances manner that an effective concentration of the active agent(s) dopamine neurotransmission temporally and spatially in in the bloodstream can be maintained over an extended both central and sympathetic nervous systems. period of time, with the concentration in the blood remaining I0083. The following examples are provided to describe relatively constant, to improve therapeutic results and/or the invention in further detail. These examples are provided minimize side effects. Additionally, a controlled-release for illustrative purposes only and are not intended to limit system would provide minimum peak to trough fluctuations the invention in any way. in blood plasma levels of the active agent. EXAMPLE 1. 0076. In the pharmaceutical compositions of the inven tion, the active agent(s) may be present in an amount of at I0084 Mediation of hyperglycemic conditions—FVB least 0.5 and generally not more than 95% by weight, based strain of mice were used in this study. In our previous study on the total weight of the composition, including carrier (unpublished), we noted that the FVB strain provides a medium and/or Supplemental active agent(s), if any. Prefer broad phenotypic window for most parameters of human ably, the proportion of active agent(s) varies between diabetic conditions similar to C57B1/6. For instance, there 30-90% by weight of the composition. was a noted weight gain and obesity induced with high and 0077. The synthesis, formulation of pharmaceutical com intermediate fat diets. A persistent high fat diet induces positions, preparation of Suitable dose forms, mode and relatively robust hyperglycemic conditions and inefficient amounts of administration of Such dopamine reuptake glucose disposal but with little noted effects on metabolic inhibitors are described in detail in U.S. Patent Application rate. There is little circadian impact and changes in activity Publication No. US 2009/0215839. patterns with the high fat diet. I0085. Twenty FVB mice (-12 weeks of age) were ran 0078. A compound that has been tested for use in the domly separated into two groups (n=10). One group (often method of the invention is 3-(phenylpropyl)-Sydnonimine mice) was fed a high fat diet (Research Diets, New Bruns N-phenylcarbamoyl, as shown in the following examples. wick, N.J., and Cat. HD 12492); with the following caloric Additional compounds that are also dopamine reuptake components: 20 percent protein; 20 percent carbohydrate; inhibitors and may be utilized in the present method include: and 60 percent fat, 5.24 kcal/gram. Another group was fed 3-(p-methylbenzyl)-sydnonimine-N-phenylcarbamoyl, with regular rodent chow (Labdiet, Richmond, Ind., product 3-(p-carboxybenzyl)-Sydnonimine-N-phenylcarbamoyl, code 5010); 28.7 percent protein, 12.7 percent fat, and 58.6 3-phenethyl-Sydnonimine-N-phenylcarbamoyl, 3-phen percent carbohydrate; 3.43 kcal/gram. After seven-weeks, ethyl-sydnonimine-N-(3',4'-dichloro-phenyl)-carbamoyl, blood glucose levels (and body weight) of the two different 3-(p-nitrophenethyl)-sydnonimine-N-(3',4'-dinitro-phenyl)- groups were examined. As shown in FIG. 1, there was a clear carbamoyl, 3-(p-fluorobenzyl)-Sydnonimine-N-phenylcar distinction between the blood glucose levels (Comparisons bamoyl, 3-benzyl-sydnonimine-N-phenylcarbamoyl, with normal chow control using Dunnett's Method, p=0. 3-phenethyl-Sydnonimine-N-(p-chlorophenyl)-carbamoyl, 0003) between the mice on the high fat diet and normal 3-phenethyl-sydnonimine-N-(m-trifluoromethyl)-phenyl chow. The group fed on the high fat diet clearly developed carbamoyl, 3-(3',5'-difluorobenzyl)-sydnonimine-N-phenyl a hyperglycemic condition. The difference in body mass was carbamoyl, 3-(m-fluorobenzyl)-Sydnonimine-N-phenylcar also clearly significant. bamoyl, 3-(p-trifluoromethyl-benzyl)-sydnonimine-N- I0086 Each of the two groups were then further separated phenylcarbamoyl, 3-(p-tert-butylbenzyl)-sydnonimine-N- into two subgroups (n=5). For the high fat diet group, the phenylcarbamoyl, 3-(p-methylbenzyl)-sydnonimine-N-(p'- separation of the animals from the hyperglycemic/high fat trifluoromethyl-phenyl)carbamoyl, and 3-(p-methylbenzyl)- diet group into two sub-groups was normalized based on the Sydnonimine-N-(p-dimethylamino-phenyl)carbamoyl. blood glucose levels. One group, designated as high fat-D, 007.9 The methods of the present invention will normally were treated with a dopamine reuptake inhibitor (3-(phenyl include medical follow-up to determine the therapeutic or propyl)-Sydnonimine-N-phenylcarbamoyl), the other group, US 2017/0056379 A1 Mar. 2, 2017

designated as high fat-N were treated with vehicle (30% acclimatized for an hour before test. Pain reflexes in captosol, 1% Tween (Tween(R) 20, a polyoxyethylene sorbi response to a thermal stimulus are measured using a Hot tan esters available from Sigma) and 1% 1N HCl in H2O: Plate Analgesia Meter from Harvard Apparatus. The plate hereafter referred to as vehicle). For the normal chow group, surface was maintained at 48° C. that was measured by a the separation was random but similarly designated and built-in digital thermometer. Mice were placed on the hot separated into drug treated (Normal-D) and vehicle controls plate which is surrounded by a clear acrylic cage with the (Normal-N). One-way ANOVA analysis of the mean values Start/Stop trigger on the timer. Latencies to respond indi is shown in FIG. 1. The high fat group remained on the high cated by shaking or licking or flicking a hind paw were fat diet; and the Normal Diet group remained on the Normal observed (If a mouse does not respond within 120 seconds, Diet for the remainder of the study. Within each dietary the test is terminated and the mouse is removed from the hot routine, there were two Sub-groups (n=5), i.e. drug treated plate) and recorded. For each subject, the test was performed and placebo/vehicle controls. three times with about 30 minute rest between tests. Animals I0087. On the 8” week of the designated dietary routine, were tested one at a time and were not habituated to the both drug-treated groups were given 3-(phenylpropyl)-Syd apparatus prior to testing. nonimine-N-phenylcarbamoyl at 10 mg/kg (p.o.), whereas 0091. The results were analyzed by Wilcoxon rank-sum the control groups were given an equal Volume of vehicle. testing, as shown in Table 1 To avoid any disturbance of circadian rhythm, the drug (or vehicle) administrations were carried out daily at approxi TABLE 1. mately 5 pm six days a week. 0088. After 4-weeks of treatment, the blood glucose Wilcoxon Kruskal-Wallis Tests (Rank Sums levels of the mice in different groups and their body mass Level Count Score Sum Score Mean (Mean - Mean')/Std were again examined. Notably, the body mass of the groups High Fat-D 5 33.OOO 6.600 -1528 that were on the high fat diet was still noticeably higher than High Fat-N 4 41.OOO 10.2SO O.OSO the groups on the Normal Diet regardless of the drug Normal-D 5 71.OOO 14.200 1898 exposure. The results of the blood glucose levels are differ Normal-N 5 4S.OOO 9.OOO -0.417 ent. All drug treated groups showed lower levels of blood glucose than their respective sham treated groups; more 0092. The results indicate that dopamine reuptake inhi importantly, there were no discernable differences between bition mediates the hypoalgesic (reduced pain sensation by the groups that were fed with high fat diet—drug treated and thermal stimulation) conditions induced by diabetic condi the group that was on Normal Diet with vehicle treatment. tions. A statistical analysis of the different groups is shown in FIG. 2. EXAMPLE 4 EXAMPLE 2 0093 Mediation of diabetic hypoalgesia (Tail-flick assay)—Mice were brought to the testing room, acclima 0089 Home-cage health and behavior This is not a tized and administered 3-(phenylpropyl)-Sydnonimine-N- qualitative measurement but the behavior pattern that we phenylcarbamoyl (5.0 mg/kg, p.o.) an hour before test. Pain noticed during the study. All 4 groups of animals were reflexes in response to a thermal stimulus are measured housed in pairs or trios according to stratification of either using a tail-flick analgesic meter with a built in stop-timer treated with drug or vehicle. For three of the 4 groups, e.g. from Columbus Instruments. Latencies to respond for the Normal Diet-drug-treated, Normal Diet-vehicle-treated, and thermal stimulation is recorder. For each subject, the test high-fat-diet-drug-treated, the animals appear to be healthy, was performed three times with about 30 minute rests were docile to handlers and non-aggressive with each other. between tests. Animals are tested one at a time and are not However the high-fat-diet-vehicle-treated group started to habituated to the apparatus prior to testing. develop underbelly lesions, bite marks, and aggressive 0094. The results were analyzed by Wilcoxon rank-sum behavior towards littermates. This pattern of behavior testing, as shown in Table 2. became especially noticeable after overnight fasting (in order for fasting blood glucose level). In fact, after the above TABLE 2 mentioned second examination (examination of fasting blood glucose level after 4 weeks of drug treatment), one of Wilcoxon Kruskal-Wallis Tests (Rank Sums the mice in the high-fat-diet-vehicle-treated group had to be euthanized due to wounds and lesions. The remainders (of Level Count Score Sum Score Mean (Mean - Mean')/Std the four mice) were subsequently housed individually. These High Fat-D 5 2S.OOO S.OOO -2.268 High Fat-N 4 6O.OOO 1S.OOO 1.9SO changes of behavior patterns and or behavior oddities are Normal-D 5 48.OOO 9.6OO -0.139 likely indicative of neurological changes under pre-diabetic Normal-N 5 57.000 11:400 O. 602 or diabetic conditions. In contrast to the high-fat-diet-ve hicle-treated group, the mice in the corresponding group that were treated with the dopamine reuptake inhibitor 3-(phe 0.095 The results indicate that dopamine reuptake inhi nylpropyl)-Sydnonimine-N-phenylcarbamoyl remained bition mediates the hypoalgesic (reduced pain sensation by healthy, docile and playful with littermates. thermal stimulation) conditions induced by diabetic condi tions. EXAMPLE 3 0096. With different testing methods and drug adminis tration routines, the comparative results between different 0090 Mediation of diabetic-induced hypoalgesia (Hot groups of mice have been consistent. As shown in FIGS. 3 plate assay)—Mice were brought to the testing room and and 4, there is a significant increase in latency responding to US 2017/0056379 A1 Mar. 2, 2017

thermal stimulation with the group treated with vehicle, fed liams, L., Prihoda, T. J., Palomo, T., and Oscar-Berman, on the high fat diet, and which showed signs of hypergly M. Attention-deficit-hyperactivity disorder and reward cemia and aggressive (unstressed) behavior. In other words, deficiency syndrome, Neuropsychiatric Disease and the group of mice that has been on the high fat diet without Treatment, 4:893-917 (2008). drug treatment developed hypoalgesia. In fact, this is the 0101 2. Campbell, B. C. and Eisenberg, D., Obesity, group of mice that developed phenotypic diabetic manifes Attention Deficit-Hyperactivity Disorder and the Dop tations recapitulating many aspects of the human diabetic aminergic Reward System, Coll. Antropol., 1:33-8 (2007). symptoms. 0102. 3. Gallego, M., Setién, Izquiero, M. J., Casis, O. 0097 Equally noteworthy is the comparison of the ther and Casis, E. Diabetes-Induced Biochemical Changes in mal responses between the high-fat-diet-drug-treated Sub Central and Peripheral Catecholaminergic Systems, jects (which otherwise would have developed hypoalgesia Phsiol. Res., 52:735-41 (2003). without drug intervention) and the Normal Diet-vehicle (0103 4. Morrison, J. F. B., Shehab, S., Sheen, R., Dha treated (supposedly with Normal-Nociceptive threshold). nasekeran, S., Shafiullah, M., and Mensah-Brown, E. Between these two groups, virtually no difference was Sensory and autonomic nerve changes in the monosodium observed, indicating that enhanced dopaminergic neu glutamate-treated rat: a model of type II diabetes. Exp rotransmission by the reuptake inhibitor mediated sensory Physiol, 93:213-22 (2007). neuropathy. In human this implication may indicate the 0104 5. Ramakrishan, R. Kempuraj, D., Prabhakaran, attenuation or mediation of the loss of distal sensation due K., Jayakumar, A. R., Devi, R. S., Suthanthirarajan, N., to diabetic neuropathy. and Namasivayam, A. A short-term diabetes induced 0098. A number of patent documents and non-patent changes of catecholamines and p38-MAPK in discrete documents are cited in the foregoing specification in order to areas of rat brain. Life Sciences, 77:1825-35 (2005). describe the state of the art to which this invention pertains. The entire disclosure of each of the cited documents is 0105 6. Russell, V. A., Oades, R. D., Tannock, R., incorporated by reference herein. Killeen, P. R., Auerbach, J. G., Johansen, E. B., and 0099 While various embodiments of the present inven Sagvolden, T. Response variability in Attention-Deficit/ tion have been described and/or exemplified above, numer Hyperactivity Disorder: a neuronal and glial energetics ous other embodiments will be apparent to those skilled in hypothesis. Behavioral and Brain Functions, 2:30 (2006). the art upon review of the foregoing disclosure. The present 01.06 7. United States Patent Pub. No. US2009/0215839. invention is, therefore, not limited to the particular embodi What is claimed is: ments described and/or exemplified, but is capable of con 1. A method for treatment of symptoms of Type II diabetes siderable variation and modification without departure from and delay of onset or prevention of occurrence of pathologic the scope of the appended claims. Furthermore, the transi conditions associated with Type II diabetes in a patient in tional terms "comprising”, “consisting essentially of and need thereof, said method comprising administering an “consisting of, when used in the appended claims, in amount of a dopamine reuptake inhibitor that is effective for original and amended form, define the claim scope with said treatment and said delay or prevention. respect to what unrecited additional claim elements or steps, 2. The method of claim 1, wherein said dopamine if any, are excluded from the scope of the claim(s). The term reuptake inhibitor is a compound of the formula:

(I)

C-N - +x N Ni-Fi k \ 7 N-O R R R2

“comprising is intended to be inclusive or open-ended and wherein R. R. R. R. Rs and R, independently of one does not exclude any additional, unrecited element, method, another, are substituents selected from H. C-C alkyl, step or material. The term "consisting of excludes any OH, halogen, Cs-Caryl, Co-Co aralkyl, C-C alky element, step or material other than those specified in the lthio, C-C alkoxy, SH, C-C alkenyl, C-C alkynyl, claim and, in the latter instance, impurities ordinary asso C-C cycloalkyl, CN, NO, carboxy, carbalkoxy, car ciated with the specified material(s). The term “consisting boxamido, alkylsulfonyl, alkylsulfonyloxy, aminosulfi essentially of limits the scope of a claim to the specified nyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, elements, steps or material(s) and those that do not materi aminosulfonyl, monoalkylaminosulfonyl, dialkylam ally affect the basic and novel characteristic(s) of the inosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, claimed invention. alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, aminosulfonylal LIST OF REFERENCES kyl, monoalkylaminosulfonylalkyl, dialkyaminosulfo nylalkyl, aminosulfinylalkyl, monoalkylaminosulfinyl 0100 1. Blum, K., Chen, A. L. C., Braverman, E. R., alkyl, dialkylaminosulfinylalkyl, said alkyl, alkenyl, Comings, D. E., Chen, T. J. H., Arcuri, V., Blum, S., alkynyl or cycloalkyl Substituent being optionally Sub Downs, B. W., Waite, R. L., Notaro, A., Lubar, J., Wil stituted by at least one halogen, OH, SH, NH, C-C, US 2017/0056379 A1 Mar. 2, 2017

alkylmethylamino, C-C dialkylamino, COOH, CN, trifluoromethyl)-phenylcarbamoyl, 3-(3',5'-difluorobenzyl)- NO, C-C alkyl or C-C alkoxy group, said aryland Sydnonimine-N-phenylcarbamoyl, 3-(m-fluorobenzyl)- aralkyl substituent being optionally substituted by at Sydnonimine-N-phenylcarbamoyl, 3-(p-trifluoromethyl least one halogen, OH, SH, NH, C-C alkylmethyl benzyl)-Sydnonimine-N-phenylcarbamoyl, 3-(p-tert amino, C-C dialkylamino, COOH, CN, NO, C-C, butylbenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p- alkyl or C-C alkoxy group; methylbenzyl)-sydnonimine-N-(p'-trifluoromethyl-phenyl) R. R. and R, independently of one another, represent carbamoyl, and 3-(p-methylbenzyl)-Sydnonimine-N-(p- substituents selected from H. C-C alkyl, phenyl or dimethylamino-phenyl)carbamoyl. phenyl C-C alkyl, said alkyl substituent, said phenyl 4. The method of claim 1, wherein said dopamine Substituent and said phenyl C-C alkyl Substituent reuptake inhibitor is administered in combination with a being optionally Substituted by at least one halogen, therapeutic agent for Type II diabetes selected from the OH, SH, NH, C-C alkylmethylamino, C-C dialky group consisting of glucophage, glyburide, repaglinide, lamino, COOH, CN, NO, C-C alkyl or C-C alkoxy acarbose, pramlintide and Sitagliptin. group; 5. The method of claim 4, wherein the dopamine reuptake m, n and k are independent integers from 0-4, except that inhibitor and the therapeutic agent for Type II diabetes are m+nz0; administered as separate dosage units. and the pharmaceutically acceptable salts of said com 6. The method of claim 4, wherein the dopamine reuptake pound. inhibitor and the therapeutic agent for Type II diabetes are 3. The method of claim 2, wherein said dopamine formulated for simultaneous administration to said patient. reuptake inhibitor is selected from the group consisting of 3-(phenylpropyl)-Sydnonimine-N-phenylcarbamoyl, 3-(p- 7. The method of claim 1, wherein said diabetic symptoms methylbenzyl)-Sydnonimine-N-phenylcarbamoyl, 3-(p-car are symptoms of a pre-diabetic condition. boxybenzyl)-Sydnonimine-N-phenylcarbamoyl, 3-phen 8. The method of claim 4, wherein said diabetic symptoms ethyl-Sydnonimine-N-phenylcarbamoyl, 3-phenethyl include at least hyperglycemia. sydnonimine-N-(3',4'-dichloro-phenyl)-carbamoyl, 3-(p- 9. The method of claim 1, wherein said diabetes-associ nitrophenethyl)-sydnonimine-N-(3',4'-dinitro-phenyl)- ated pathologic conditions comprise at least one selected carbamoyl, 3-(p-fluorobenzyl)-sydnonimine-N- from the group of diabetic sensory neuropathy, diabetic phenylcarbamoyl, 3-benzyl-sydnonimine-N- autonomic neuropathy, diabetic retinopathy, diabetic neph phenylcarbamoyl, 3-phenethyl-sydnonimine-N-(p- ropathy and diabetic angiopathy. chlorophenyl)-carbamoyl 3-phenethyl-Sydnonimine-N-(m- k k k k k