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(12) United States Patent (10) Patent No.: US 9,365,532 B1 Isaacman (45) Date of Patent: Jun

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(12) United States Patent (10) Patent No.: US 9,365,532 B1 Isaacman (45) Date of Patent: Jun USOO9365.532B1 (12) United States Patent (10) Patent No.: US 9,365,532 B1 Isaacman (45) Date of Patent: Jun. 14, 2016 (54) SYNTHESIS, COMPOSITION AND USE OF Chemical Abstracts entry for JP62-153212. (Katsuta et al.) originally NOVEL THERAPEUTIC AND COSMETC published Jul. 8, 1987.* SCHIFF BASE PRODUCTS FORMED BY Drugarinet al., “Synthesis of new hippuric acid derivatives, Part 2. REACTION OF A CARBONYL CONTAINING Azomethines of hippuric acid esters' Pharmazie (1981) vol.36 No. 4 pp. 302-303.* MOEITY WITH A TRANSIMINATION Topich et al., “Monomeric Polymer-Anchored Molybdenum(V) NUCLEOPHILIC CATALYST AND THE USE Coordination Complexes” Inorganic Chemstry (1982) vol. 21 pp. OF TRANSIMINATION NUCLEOPHILC 2O79-2O82.* CATALYSTS TO INCREASE THE RATE AT Salon et al., “Fluoroimines from the reaction of fluoroamino acids or WHICH CARBONYL CONTAINING fluoroketo acids with the aldehyde or amine form of vitamin B6: part THERAPEUTIC AND COSMETIC ACTIVES III. Influence of fluorine on the formation and the reactivity of FORMSCHIFF BASE PRODUCTS WITH fluoroimines derived from beta-fluoroaspartates or beta BOLOGICAL AMNES fluorooxaloacetate” Journal of Fluorine Chemistry (1985) vol. 27 No. 4 pp. 361-370.* Wyler et al., “Urnwandlung eines Betacyans in ein Betaxanthin (75) Inventor: Steven Isaacman, New York, NY (US) Synthese von Indicaxanthin aus Betanin' Helvetica Chimica Acta (1965) vol. 48 no. 2 pp.39-40.* (73) Assignee: Nanometics, LLC., New York, NY (US) Johnson et al., “Reaction of Hydantoin with Acetals” Journal of Organic Chemistry (1962) vol. 27 pp. 2077-2080.* (*) Notice: Subject to any disclaimer, the term of this Deng et al., “Microwave Synthesis of Schiff-Base Complexes and patent is extended or adjusted under 35 Organic Tin' Advanced Materials Research (2011) vol. 201-203, pp. U.S.C. 154(b) by 813 days. 2550-2553. * Barluenga et al., “Regioselective Synthesis of 4,6,7-Trisubstituted (21) Appl. No.: 13/396,221 Benzofurans from Furfural Imines and Nonheteroatom Stabilized Alkynylcarbene Complexes” J. Am. Chem. Soc. (2009) vol. 131 pp. (22) Filed: Feb. 14, 2012 14628-14629. Related U.S. Application Data * cited by examiner (60) Provisional application No. 61/442.432, filed on Feb. Primary Examiner — Eric Olson 14, 2011, provisional application No. 61/502.466, (74) Attorney, Agent, or Firm — Henry D. Coleman: R. Neil filed on Jun. 29, 2011. Sudol (51) Int. Cl. (57) ABSTRACT C07D 307/52 (2006.01) CO7D 333/22 (2006.01) The present invention relates to the synthesis, composition C07D 207/335 (2006.01) and use of novel moieties formed by reacting a transimination C07C 251/20 (2006.01) nucleophilic catalyst, molecular or polymeric, with carbonyl (52) U.S. Cl. containing therapeutic or cosmetic moieties. The resultant CPC ............ C07D 307/52 (2013.01); C07C 251/20 Schiffbase product is highly reactive towards transimination (2013.01); C07D 207/335 (2013.01); C07D with a biological amine. The catalyst and carbonyl-contain 333/22 (2013.01) ing moiety can be molecular or polymeric, and the resultant (58) Field of Classification Search chemical and physical properties of the Schiff base products CPC. C07C 251/20; C07D 307/52; C07D 333/22 can be engineered by appropriate selection of said catalyst. See application file for complete search history. The present invention also relates to the synthesis, composi tion and use of novel moieties that are used as actives in (56) References Cited Sunless tanning preparations. The present invention also relates to the use of transimination nucleophilic catalysts to U.S. PATENT DOCUMENTS increase the rate at which a carbonyl-containing moiety reacts with a biological amine. The present invention also relates to 5,744,598 A * 4, 1998 Skalkos et al. ................ 540,472 the use of transimination nucleophilic catalysts to increase OTHER PUBLICATIONS the rate and efficacy of commercial Sunless tanning prepara tions. Improvements on stability and efficacy of said prepa Dursun et al., Glasnik Hemicara ithecnologa Bisne i Hersegovine rations are disclosed. While the invention has been described (1969) No. 17 pp.39-41.* in terms of its preferred embodiments, those skilled in the art Chemical Abstract Registry entries 904626-23-9, 904626-21-7. will recognize that the invention can be practiced with modi 342020-73-9, and 342020-72-8, entered into STN Aug. 25, 2006, Aug. 24, 2006, and Jun. 18, 2001, respectively.* fication within the spirit and scope of the appended claims. Sosnovskikh et al., “Structure of reaction products of Accordingly, the present invention should not be limited to 3-cyanochromones with ethylenediamine” Russion Chemical Bulle the embodiments as described above, but should further tin, International Edition (2010) vol. 59 No. 11 pp. 2151-2154.* include all modifications and equivalents thereof within the Roy et al., “Dioxouranium(VI) complexes of N-(orthovanillidene)- spirit and scope of the description provided herein. anthranilic acid and N-(vanillidene)-anthranilic acid” Transition Metal Chemistry (1987) vol. 12 pp. 137-140.* 16 Claims, 8 Drawing Sheets U.S. Patent Jun. 14, 2016 Sheet 1 of 8 US 9,365,532 B1 IGURE 1 |L^) L^) E XI |I XI LL 5m N1 AIC }DnppV/CH/HWNH9% U.S. Patent Jun. 14, 2016 Sheet 2 of 8 US 9,365,532 B1 FIGURE 2 2m MSHMF 2mM 5HMF + 2mM PABA 5mm 5HMF 5mM 5HMF + 5 mM PABA O minutes Time 30 minutes U.S. Patent Jun. 14, 2016 Sheet 3 of 8 US 9,365,532 B1 FIGURE 3 200mg/kg 5HMF + 200m 5% - L SQ O minutes 30 minutes Time U.S. Patent Jun. 14, 2016 Sheet 4 of 8 US 9,365,532 B1 FIGURE 4 IV \ o Tucaresol AIC.4423 0 U.S. Patent Jun. 14, 2016 Sheet 5 of 8 US 9,365,532 B1 FIGURES 2050 Competitive Binding Assay | o 2OOO PABA Control 1950 500 uMi Tuca resol 3 1900 5OOuM Tucaresol 3. + 1 mM PABA O 1850 B 1800 f G | 2 1750 U.S. Patent Jun. 14, 2016 Sheet 6 of 8 US 9,365,532 B1 FIGURE 6A and B Rate of color change is faster in the presence of PABA 8 0.60 9 3 i 0.5 3. O 45 90 35 80 400 cóo 400 so Time (min) Wavelength (nm) U.S. Patent Jun. 14, 2016 Sheet 7 of 8 US 9,365,532 B1 FIGURE 7 In Vivo clinical studies U.S. Patent Jun. 14, 2016 Sheet 8 of 8 US 9,365,532 B1 FIGURE 8 TABLE 2 LEFT RIGHT HMFHA. Add Unmodified Hbs on with H. t US 9,365,532 B1 1. 2 SYNTHESIS, COMPOSITION AND USE OF are distorted and become rigid and sickle-shaped (1). The NOVEL THERAPEUTIC AND COSMETIC genetic mutation is manifested physiologically as the altered SCHIFF BASE PRODUCTS FORMED BY morphologically sickled RBC occlude circulation, resulting REACTION OF A CARBONYL CONTAINING in localized ischemia, infarction, hemolytic anemia, organ MOEITY WITH A TRANSIMINATION 5 damage and other debilitating acute and chronic effects (1). NUCLEOPHILIC CATALYST AND THE USE While the frequency, severity and duration of vaso-occlusive OF TRANSIMINATION NUCLEOPHILIC crises can vary amongst individuals, the episodes are CATALYSTS TO INCREASE THE RATEAT extremely painful, recurrent and lead to a high rate of hospi WHICH CARBONYL CONTAINING talization and use of acute medical care facilities, with annual THERAPEUTIC AND COSMETIC ACTIVES 10 costs to the global healthcare system (3). The pain crisis is the FORMSCHIFF BASE PRODUCTS WITH hallmark feature of the disease, interfering profoundly with BOLOGICAL AMINES functioning and has defied all attempts to intervene with drugs that target the sickling process (4). One promising RELATED APPLICATIONS approach to treat acute episodes involves the use of aryl 15 aldehydes that interact stoichiometrically with the N-terminal This application claims the benefit of priority of provi amino group of C-Vall of HbS, increasing the oxygen affinity sional application Ser. No. US61/442.432, filed Feb. 14, and inhibiting the sickling of homozygous sickle red blood 2011, entitled “Synthesis, Composition and Use of Novel cells by affecting allosteric oxy-deoxy conformational tran Therapeutic and Cosmetic Schiff Base Products Formed by sitions (6). The resultant Schiff base adduct is thought to be Reaction of a Carbonyl Containing Moiety With a Transimi- 20 stabilized by intramolecular interactions between structural nation Nucleophilic Catalyst and the Use of Transimination aspects of oxy-Hb at the O.C.-end of the central cavity (6). Nucleophilic Catalysts to Increase the Rate at which Carbo Preclinical studies with various aldehydes have shown prom nyl Containing Therapeutic and Cosmetic Actives Form ise in vitro where the hypoxia-induced formation of sickle Schiff Base Products with Biological Amines, and provi cells was largely inhibited by high concentrations of aldehyde sional application Ser. No. US61/502.466, filed Jun. 29, 25 (7). In addition, certain aldehydes have been shown to pro 2011, entitled 'Acceleration of In Vivo Schiff Base Forma long the Survival time of mice exposed to severe hypoxia and tion, Compounds Related Thereto and Therapeutic Uses can exhibit favorable pharmacokinetic properties including Thereof, each of which applications is incorporated by refer oral bioavailability, rapid absorption into the blood stream, ence in its entirety. and high specificity for HbS (7). The clinical utility of these 30 aldehydes requires high concentrations to compensate for the FIELD OF THE INVENTION slow rate of Schiff base adduct (aldehyde/Hemoglobin) for mation at hemoglobin and it would be advantageous to The present invention relates to the synthesis, composition increase the rate of reaction, and thereby decrease the con and methods for use of imines (Schiff bases) and iminium centration of therapeutic needed for efficacy. cations formed by reacting a transimination nucleophilic 35 As another non-limiting example, aldehyde-containing catalyst, with aldehyde or ketone containing molecules, and molecules can be used as adjuvants to other interventions their use to treat disease or impart color change on the skin.
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