DERIVATIZED BENZIMIDAZOLE COMPOUNDS, THEIR SALTS, THEIR COMPLEXES, THEIR PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USING THEM FOR ANTIGERIATRIC ACTIONS

Abstract

Embodiments of the present invention generally concern pharmaceutical formulations and compositions and methods for using the pharmaceutical formulations and compositions which comprise derivatives of benzimidazole compounds, their racemic mixtures, their enantiomers, their complexes, their salts, and combinations thereof which have been found to be novel agonists of imidizoline receptors with surprising life extending efficacies due to their geroprotective (anti-geriatric) actions on pathologies associated with the aging processes in humans and animals.

Claims

1. A compound of Formula (1), a racemic mixture of the compound of the Formula (1), an enantiomer of the compound of the Formula (1), a salt of the compound of the Formula (1), a complex of the compound of the Formula (1), and any combination thereof, the compound of the Formula (1) comprising: ##STR00023## wherein substituents R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5, Br, Cl, I, F, OH, CN, NO.sub.2, COOH, and any combination thereof, wherein substituent R.sub.5 selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5, wherein substituent R.sub.6 is selected from the group consisting of ##STR00024## wherein substituents R.sub.13 and R.sub.14 are selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5, and any combination thereof, wherein substituent Ru is selected from the group consisting of CH.sub.3, ##STR00025##

2. The compound according to claim 1, wherein the compound is a salt selected from the group consisting of a hydrochloride, a hydrobromide, a hydroiodide, a sodium salt, a potassium salt, a lithium salt, a magnesium salt, a calcium salt, an iron salt, a copper salt, a zinc salt, an aluminum salt, a sulfate, a nitrate, a hydrogen phosphate, a phosphate, an acetate, a propionate, a hexanoate, cyclopentanepropionate, glycolate, a pyruvate, a lactate, malonate, a succinate, maliate, maleate, fumarate, tartrate, a citrate, benzoate, 3-(4-hydroxybenzoyl) benzoate, cinnaminate, mandelate, methanesulfonate, a besylate, an ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tertiary butylacetate, lauryl sulfate, gluconate, glutamate, hydroxynaphthate, salicylate, stearate, muconate, a coordination complex with ethanolamine, a coordination complex with diethanolamine, a coordination complex with triethanolamine, a coordination complex with N-methylglucamine, a coordination complex with NTA, a coordination complex with HEPTA, a coordination complex with EGTA, a coordination complex with EDTA, a 2-napsylate, a 3-hydroxy-2-naphthoate, a 3-phenylpropionate, a 4-acetamidobenzoate, an acefyllinate, an aceturate, an adipate, an alginate, an aminosalicylate, an ammonium, an amsonate, an ascorbate, an aspartate, a bicarbonate, a bisulfate, a bitartrate, a borate, a butyrate, a calcium edetate, a camphocarbonate, a camphorate, a camsylate, a carbonate, a cholate, a clavulariate, a cyclopentane-propionate, a cypionate, a d-aspartate, a d-camsylate, a d-lactate, a decanoate, a dichloroacetate, a digluconate, a dodecylsulfate, an edisylate, an estolate, an esylate, an ethyl sulfate, a furate, a fusidate, a galactarate, a mucate, a galacturonate, a gallate, a gentisate, a gluceptate, a glucoheptanoate, a gluconate, a glucuronate, a glutamate, a glutarate, a glycerophosphate, a glycolate, a glycollylarsanilate, a hemisulfate, a heptanoate, an enanthate, a heptanoate, a hexafluorophosphate, a hexanoate, a hexylresorcinate, a hippurate, a hydrabenzate, a hydrabamine, a hydroxybenzoate, a hydroxynaphthoate, a chloride, a bromide, an iodide, a fluoride, an isethionate, an isothionate, an 1-aspartate, a 1-camsylate, an 1-lactate, a lactate, a lactobionate, a laurate, a laurylsulphonate, a meso-tartrate, a mesylate, a methanesulfonate, a methylbromide, a methylnitrate, a methylsulfate, a myristate, an N-methylglucamine an ammonium salt, a napadisilate, a naphthylate, a napsylate, a nicotinate, an octanoate, an oleate, an orotate, an oxalate, a palmitate, a pamoate, a pantothenate, a pectinate, a persulfate, a phenylpropionate, a phosphateldiphosphate, a picrate, a pivalate, a polygalacturonate, a pyrophosphate, a saccharate, a salicylsulfate, a subacetate, a sulfosaliculate, a sulfosalicylate, a suramate, a tannate, a teoclate, a terephthalate, a thiocyanate, a thiosalicylate, a tosylate, a tribrophenate, a triethiodide, an undecanoate, an undecylenate, a valerate, a valproate, a xinafoate, thioctic acid salt, a choline salt, a folate, and a combination thereof.

3. The compound according to claim 2, wherein the compound is the hydrochloride salt or is the thioctic acid salt.

4. The compound according to claim 2, wherein the compound is in a mixture with choline.

5. The compound according to claim 2, wherein the compound is the magnesium salt.

6. The compound according to claim 1, wherein the compound is in a complex with dapagliflozin.

7. The compound according to claim 1, wherein the compound is in a complex with 3-(1H-benzimidazol-2-yl)-1,2,2-trimethylcyclopentanecarboxylic acid.

8. The compound according to claim 1, wherein the compound is administered with metformin to a human or to an animal.

9. A method of administering a dose of the compound according to claim 1 in a pharmaceutical formulation by a route of administration as a means for using the compound to provide a medical treatment to a human or an animal.

10. The method according to claim 9, wherein the dose of the compound is a milligram dose selected from the group consisting of about 0.05 mg to about 0.5 mg, about 0.5 mg to about 50 mg, about 50 mg to about 500 mg, about 500 mg to about 5,000 mg, and any combination thereof.

11. The method according to claim 9, wherein the pharmaceutical formulation is selected from the group consisting of a parenteral pharmaceutical formulation, an injection solution pharmaceutical formulation, an injection suspension pharmaceutical formulation, a multiple dose vial pharmaceutical formulation, a compressed tablet pharmaceutical formulation, a coated tablet pharmaceutical formulation, a sugar-coated tablet pharmaceutical formulation, a soft gelatin capsule pharmaceutical formulation, a gelatin capsule pharmaceutical formulation, a pill pharmaceutical formulation, a cachet pharmaceutical formulation, a powder pharmaceutical formulation, a suppository pharmaceutical formulation, a rectal capsule pharmaceutical formulation, an oral solution pharmaceutical formulation, an oral suspension pharmaceutical formulation, a topical ointment pharmaceutical formulation, a topical crème pharmaceutical formulation, a topical liquid pharmaceutical formulation, an extended release pharmaceutical formulation, a slow release pharmaceutical formulation, a transdermal patch pharmaceutical formulation, a micronized aerosol pharmaceutical formulation for inhalation, an intravenous pharmaceutical formulation, a topical balm pharmaceutical formulation, a topical gel pharmaceutical formulation, and any combination thereof.

12. The method according to claim 9, wherein the route of the administration is selected from the group consisting of a parenteral route, an intramuscular route, a subcutaneous route, an epidural route, an intracerebral route, a subthecal route, an intravenous route, a cardiac ventricular or atrial chamber route, a coronary artery route, a pulmonary route, a visceral cavity route, an oral route, a rectal route, an intrauterine cavity route, an intravaginal route, an intraurethral route, a sublingual route, a permucous route, an eye drop route, an intraocular route, an inhalation route, an in-dwelling cannula route, an arterial cannula route, a venous cannula route, an intranasal route, a transdermal route, and any combination thereof.

13. The method according to claim 9, wherein the medical treatment to the human or the animal is selected from the group consisting of an cancer reducing treatment, a cancer prevention treatment, an anti-geriatric treatment, an anti-aging treatment, a kidney nephron protecting treatment, a cardiac muscle protecting treatment, an anti-arrhythmia treatment, a cardiac ischemia preventing treatment, a brain ischemia protecting treatment, a dementia treatment, a cerebroprotector treatment, a hepatoprotector treatment, an antihypertension treatment, a diabetes treatment, a diabetes preventing treatment, a body mass index lowering treatment, a tissue insulin sensitivity increasing treatment, an inflammatory disease reducing treatment, a preventative eye pathology treatment, a pregnancy eclampsia prevention treatment, an aerobic fitness improving treatment, a weight loss assisting treatment, a tissue ischemia preventing treatment, an organ ischemia preventing treatment, a tissue hypoxia preventing treatment, an organ hypoxia preventing treatment, an tissue edema preventing treatment, a cardiac hypertrophy pathology preventing treatment, a cardiac myopathy preventing treatment, a pituitary gland pathology preventing treatment, a pancreatic pathology preventing treatment, a thyroid pathology preventing treatment, and a combination thereof.

14. The method according to claim 9, wherein the medical treatment to the human or the animal is for treating a pathology selected from the group consisting of a peripheral vascular resistance pathology, a renin-angiotensin system pathology, a salt and water retention pathology, and any combination thereof.

15. The method according to claim 9, wherein the medical treatment to the human or the animal is for treating a pathology selected the group consisting of the pathology arising from a radiation treatment to the human or the animal, the pathology arising from a chemotherapy treatment to the human or the animal, the pathology arising from an immunotherapy treatment to the human or the animal, the pathology arising from the human or the animal having cancer, the pathology arising from the human or the animal having a test to detect a cancer presence, the pathology arising from the human or the animal having an adverse reaction to a biopsy sample taken from them, and any combination thereof.

16. The method according to claim 9, wherein the medical treatment to the human or the animal is selected from the group consisting of a reducing wrinkling of the skin treatment, a reducing hair loss treatment, a plastic surgery tissue treatment, a reducing wound scaring treatment, an improving wound healing treatment, an increasing a tissue blood circulation treatment, an increasing an organ blood circulation treatment, an improving a muscle tone treatment, a reducing a fat accumulation treatment, and any combination thereof.

17. The method according to claim 9, wherein the dose of the compound administered is used for treating a pathology caused by an aging of the body of the human or the animal, and wherein the treating of the pathology is related to activating imidazoline receptors in the body of the human or the animal.

18. The method according to claim 9, wherein the dose of the compound administered is used for causing a measureable therapeutic effect to the human or the animal, and wherein the measureable therapeutic effect can be measured by a test conducted at a hospital, a medical clinic, by a medical doctor, or by a blood analysis test laboratory.

19. An anti-geriatic compound selected from the group consisting of the compounds IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh, Vi, VIIa, VIIb, VIIc, VIId, VIIe, VIIf, VIIg, VIIh, VIIi, IXa, IXb, IXc, IXd, IXe, IXf, IXg, Xia, XIb, XIc, XId, XIe, XIf, XIg, XIh, Xii, XIIIa, XIIIb, XIIIc, XIIId, XIIIe, XIIIf, XIIIg, XIIIh, XIIIi, XVa, XVb, XVc, XVd, XVe, XVf, XVg, XVh, and XVi.

20. The anti-geriatric compound according to claim 19, wherein the anti-geriatric compound is selected from the group consisting of the compounds IIIh, IXa, IXb, Xia, XIIIh, XVa, XVg, XVh, and XVi.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0038] It is an important objective of some embodiments of the present invention to provide compounds which are new and effective derivatives of benzimidazole, their racemic mixtures, theire enantiomers, their complexes, their salts, and a combination thereof wherein the compounds exhibit anti-geriatric actions, the compounds comprising the below Formula 1 Structure:

##STR00005##

wherein substituent R.sub.1-4 is selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5, Br, Cl, I, F, OH, CN, NO.sub.2, and COOH,
wherein substituent R.sub.5 is selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5,
wherein substituent R.sub.6 has a chemical structure selected from the group consisting of

##STR00006##

wherein substituent R.sub.13,14 is selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5 and
wherein substituent R.sub.12 is selected from the group consisting of CH.sub.3,

##STR00007##

The present invention includes embodiments which are a salt of a Formula 1 compound. Example salts of a Formula 1 compound include a salt selected from the group consisting hydrochloride salts, hydrobromide salt, hydroiodide salt, sodium salt, potassium salt, magnesium salt, calcium salt, iron salt, and a copper salt. Additional examples of Formula 1 compounds and their salts their combination as a pharmaceutical formulation including a compound selected from the group consisting of thioctic acid, metformin, choline, dapagliflozin, and a complex with 3-(1H-benzimidazol-2-yl)-1,2,2-trimethylcyclopentanecarboxylic acid. Complexes and salts of the Formula 1 compounds are useful for manufacturing drugs including AIRs which are selective activators and/or agonists of imidazoline receptors for the treatment of pathologies caused by aging.

[0039] Based on these structures, an effective dose amount of pharmaceutical compositions of the Formula 1 compounds, salts, complexes and combinations of chemical substance named above, optionally formulated with one or more pharmaceutically acceptable excipients, are particularly useful therapeutic compositions for administration to a person as a method of treating one or more pathologies associated with or believed to be caused by an aging of the body of the person, Some effective dose amounts are an effective amount of between about 0.05 mg to 10,000 mg, preferably between about 0.5 mg to about 1,000 mg.

[0040] Separately, the composition may contain, as a mixture, thioctic acid, metformin, choline, dapagliflozin, 3-(1H-benzimidazol-2-yl)-1,2,2-trimethylcyclopentane carboxyl-ic acid alone or in a mixture with each other. Said pharmaceutical compositions can be used in various dosage forms as a pharmaceutical formulation which is selected from the group consisting of a parenteral formulation, an injection solution, an injection suspension, a multiple dose vial formulation, a plain tablet, a coated tablet, a sugar-coated tablet, a plate capsule, a gel capsule, a pill, a cachet, a powder, a suppository, a rectal capsule, an oral solutions, an oral suspensions, a topical ointment, a transdermal patch, a micronized aerosol formulation for inhalation, an intravenous formulation, a topical formulation, and a topical gel.

[0041] The pharmaceutical compositions of the present invention in some embodiments are administered by a route selected from the group consisting of parenteral, intramuscular, intracerebral, intravenous, intracardiac, oral, rectal, permucous, eye drop, inhalation, in-dwelling cannula, coronary cannula, arterial cannula, venous cannula, intranasal, and transdermal. The uses of some embodiments of the present invention are designed as pharmaceutical drugs for the treatment of pathologies by the aging process as drugs functioning as therapeutic agents selected from the group consisting of anticancer agents, life prolongation agents, nephroprotector agents, cardioprotector agents, cerebroprotector agents, hepatoprotector agents, antihypertensive agents, as agents that increase the sensitivity of tissues to insulin, and a combination thereof.

Example 1: Synthesis of Formula 1 Compound Derivatives (III)

[0042] ##STR00008##

[0043] A mixture of 2.05 g (0.01 mole) of thioctic acid (I), 1.08 g of 0.01 mole) substituted ortho-phenylenediamine (II), 15 ml of glacial acetic acid and 5 ml of dimethylformamide was boiled for 60 minutes. The solution was cooled, the formed precipitate (III) is filtered off and dried, and then crystallized from ethanol. The yield was 70-85%.

[0044] Instead of unsubstituted (II), its substituted derivatives can be made with R.sub.1-4 as H, CH.sub.3, C.sub.2H.sub.5, Br, Cl, I, F, OH, CN, NO.sub.2, or COOH and with R.sub.5 as H, CH.sub.3, C.sub.2H.sub.5, or I.

[0045] Instead of glacial acetic acid, a mixture of 1.5 ml of toluene and 5 ml of dimethylformamide can be used. Instead of recrystallization, precipitation from a solution of glacial acetic acid with isopropyl alcohol can be used by adding 5 ml of isopropyl alcohol to the cooled reaction mixture and settling the solution for a day. The precipitate that formed can be filtered off and reprecipitated from glacial acetic acid with isopropanol as described above. Table 1 below tabulates the analysis data for some of the synthesized Formula 1 Compound Derivatives (III).

TABLE-US-00001 TABLE 1 Results of NMR .sup.13C Analysis of some of the Synthesized Formula 1 Compound Derivatives (III) and their Percent (%) Synthesis Yields: Substance % Yield Code Substituents NMR .sup.13C, PPM Theoretical IIIa R.sub.1-5 = H 56.3(CH); 38.5(CH.sub.2); 138.9(C); 85 ± 10 151.4(C); 40.2(CH.sub.2); 115.2(CH); 123.0(CH); 34.9(CH.sub.2); 29.2(CH.sub.2); 25.2(CH.sub.2); 22.1(CH.sub.2) IIIb R.sub.1-3,5 = H, 56.3(CH); 38.5(CH.sub.2); 138.9(C); 77 ± 10 and 151.4(C); 129.5(C); 138.8(C); R.sub.4 = COOH 40.2(CH.sub.2); 125.6(CH) 120.4(CH); 122.9(CH) 166.4(C);; 34.9(CH.sub.2); 29.2(CH.sub.2); 25.2(CH.sub.2); 22.1(CH.sub.2) IIIc R.sub.1,3-5 = H, 56.3(CH); 38.5(CH.sub.2); 151.4(C); 80 ± 10 and 142.5(C); 138.7(C); 40.2(CH.sub.2); R.sub.2 = NO.sub.2 144.3(C); 112.9(CH); 116.1(CH); 118.6(CH); 34.9(CH.sub.2); 29.2(CH.sub.2); 25.2(CH.sub.2); 22.1(CH.sub.2) IIId R.sub.1,3,5 = H, 56.3(CH); 38.5(CH.sub.2); 151.4(C); 79 ± 10 and 138.7(C); 135.4(C); 40.2(CH.sub.2); R.sub.2,4 = CH.sub.3 126.1(C); 112.3 (CH); 132.6(C); 124.3(CH); 29.2(CH.sub.2); 16.5(CH.sub.3); 21.6(CH.sub.3); 25.2 (CH.sub.2); 22.1(CH.sub.2) IIIe R.sub.1,3,5 = H, 56.3(CH); 38.5(CH.sub.2); 148.2(C); 80 ± 10 and 128.8(C); 119.4(CH); 40.2(CH.sub.2); R.sub.2,4 = Br 122.3(C); 127.9(CH); 34.9(CH.sub.2); 28.8(CH.sub.2); 136.9(CH); 116.1(CH.sub.2); 25.2(CH.sub.2); 22.1(CH.sub.2) IIIe R.sub.1,3,5 = H, 56.3(CH); 38.5(CH.sub.2); 151.4(C); 85 ± 10 and 141.7(C); 136.4(CH); 40.2(CH.sub.2); R.sub.2,4 = Cl 122.1(C); 130.6 (C); 113.9(CH); 123.7(CH); 34.9(CH.sub.2); 29.2(CH.sub.2); 25.2(CH.sub.2); 22.1(CH.sub.2) IIIf R.sub.1,3 = H, 56.3(CH); 38.5(CH.sub.2); 151.4(C); 75 ± 10 and 153.0(C); 138.7(C); 135.6(C); R.sub.2,4,5 = CH.sub.3 40.2(CH.sub.2); 126.1(C); 112.3(CH); 132.6(C); 124.3(CH); 32.3(CH.sub.3); 34.9(CH.sub.2); 26.7(CH.sub.2); 16.8(CH.sub.3); 21.6(CH.sub.3); 25.2(CH.sub.2); 22.4(CH.sub.2) IIIg R.sub.1,2,4 = H, 56.3(CH); 38.5(CH.sub.2); 154.7(C); 80 ± 10 R.sub.3 = F, 137.8(C); 135.8(C); 40.2(CH.sub.2); and 156.5(C); 102.4(CH); 116.8(CH); R.sub.5 = C.sub.2H.sub.5 109.9(CH); 40.4(CH.sub.2); 34.9(CH.sub.2); 27.0(CH.sub.2); 25.2(CH.sub.2); 22.4(CH.sub.2); 15.1(CH.sub.3) IIIh R.sub.1,4 = H, 56.3(CH); 38.5(CH.sub.2); 141.5(C); 85 ± 10 R.sub.3 = I, 132.1(C); 139.2(C); 40.2(CH.sub.2); R.sub.2 =OH, 78.9(C); 160.6(C); 125.7(CH); and 104.0(CH); 34.9(CH.sub.2); 27.7(CH.sub.2); R.sub.5 = I 25.2(CH.sub.2); 21.2(CH.sub.2)

Example 2: Synthesis of Formula 1 Compound Derivatives (V)

[0046] ##STR00009##

[0047] A mixture of 3.9 g (0.01 mole) ursodeoxycholic acid (IV), 1.08 g (0.01 mole) ortho-phenylenediamine (II), 10 ml of glacial acetic acid and 3 ml of dimethylformamide was boiled for 90 minutes. The solution was cooled, the formed precipitate (V) was filtered off and dried, and then was crystallized from methanol. The yield was 70-85%.

[0048] Instead of unsubstituted (II), its substituted derivatives can be made with R.sub.1-4 as .sub.MH, CH.sub.3, C.sub.2H.sub.5, Br, Cl, I, F, OH, CN, NO.sub.2, or COOH, and with R.sub.5 as H, CH.sub.3, C.sub.2H.sub.5, or I.

[0049] Instead of glacial acetic acid, a mixture of 9 ml of toluene and 9 ml of dimethylformamide can be used. Instead of recrystallization, precipitation from a solution of glacial acetic acid with isopropyl alcohol can be used by adding 5 ml of water to the cooled reaction mixture and settling the solution for a day. The precipitate that formed is filtered off can be re-precipitated from glacial acetic acid with water as described above. Table 2 below tabulates the analysis data for some of the synthesized Formula 1 Compound Derivatives (V).

TABLE-US-00002 TABLE 2 Results of .sup.13C NMR Analysis of some of the Synthesized Formula 1 Compound Derivatives (V) and their Percent (%) Synthesis Yield Percentages Substance % Yield Code Substituents NMR .sup.13C, PPM Theoretical Va R.sub.1-5 = H 151.4(C); 139.9(C); 138.9(C); 60 ± 10 43.0(C); 50.4(CH); 56.3(CH); 24.5(CH.sub.2); 28.3(CH.sub.2); 68.4CH); 71.4(CH); 115.2(CH); 40.0(CH); 40.2(CH.sub.2); 123.0(CH); 35.8(C); 41.9(CH); 41.1(CH); 37.4(CH); 30.9(CH.sub.2); 21.0(CH.sub.2); 35.6(CH.sub.2); 35.4(CH); 27.0(CH.sub.2); 13.6(CH.sub.3); 38.9(CH.sub.2); 19.3(CH.sub.3) Vb R.sub.1-3,5 = H, 151.4(C); 138.8(C); 129.5(C); 52 ± 10 and 43.0(C); 50.4(CH); 56.3(CH); R.sub.4= COOH 24.5(CH.sub.2); 28.3(CH.sub.2); 68.4(CH); 71.4(CH); 117.5(CH); 120.4(CH); 40.0(CH); 40.2(CH.sub.2); 125.6(CH); 122.9(CH); 35.8(C); 41.9(CH); 41.1(CH); 37.4(CH); 30.9(CH.sub.2); 21.0(CH.sub.2); 35.6(CH.sub.2); 166.4(C); 35.40(CH); 27.0(CH.sub.2); 13.6(CH.sub.3); 38.9(CH.sub.2); 19.4(CH.sub.3) Vc R.sub.1,3-5 = H, 151.4(C); 139.8(C);135.4(C); 55 ± 10 and 43.0(C); 50.4(CH); 56.3(CH); R.sub.2 = NO.sub.2 24.5(CH.sub.2); 28.3(CH.sub.2); 68.4(CH); 71.4(CH); 126.1(C); 112.3(CH); 40.0(CH); 40.2(CH.sub.2); 118.6(CH); 123.9(CH); 35.8(C); 41.9(CH); 41.1(CH); 37.4(CH); 30.9(CH.sub.2); 21.0(CH.sub.2); 35.6(CH.sub.2); 35.40(CH); 27.0(CH.sub.2); 13.6(CH.sub.3); 38.9(CH.sub.2); 19.4(CH.sub.3) Vd R.sub.1,3,5 = H, 151.4(C); 138.7(C);133.7(C); 50 ± 10 and 43.0(C); 50.4(CH); 56.3(CH); R.sub.2,4 = CH.sub.3 24.5(CH.sub.2); 28.3(CH.sub.2); 68.4(CH); 71.4(CH); 137.0(C); 121.3(CH); 40.0(CH); 40.2(CH.sub.2); 132.6(C); 124.3(CH); 35.8(C); 41.9(CH); 41.1(CH); 37.4(CH); 30.9(CH.sub.2); 21.0(CH.sub.2); 35.6(CH.sub.2); 35.40(CH); 27.0(CH.sub.2); 13.6(CH.sub.3); 16.5(CH.sub.3); 21.6(CH.sub.3); 13.5(CH.sub.3); 38.9(CH.sub.2); 19.4(CH.sub.3) Ve R.sub.1,3,5 = H, 151.4(C); 141.7(C); 136.4(C); 45 ± 10 And 43.0(C); 50.4(CH); 56.3(CH); R.sub.2,4 = Cl 24.5(CH.sub.2); 28.3(CH.sub.2); 122.1(C); 130.6(C); 68.4(CH); 71.4(CH); 113.9(CH); 40.0(CH); 40.2(CH.sub.2); 123.7(CH); 35.8(C); 41.9(CH); 41.1(CH); 37.4(CH); 30.9(CH.sub.2); 21.0(CH.sub.2); 35.6(CH.sub.2); 35.40(CH); 27.0(CH.sub.2); 13.6(CH.sub.3); 13.5(CH.sub.3); 38.9(CH.sub.2); 19.4(CH.sub.3) Ve R.sub.1,3,5 = H, 151.4(C); 143.3(C); 140.2(C); 60 ± 10 and 43.0(C); 50.4(CH); 56.3(CH); R.sub.2,4 = Br 24.5(CH.sub.2); 28.3(CH.sub.2); 112.2(C); 119.7(C); 68.4(CH); 71.4(CH); 117.7(CH); 40.0(CH); 40.2(CH.sub.2); 129.5(CH); 35.8(C); 41.9(CH); 41.1(CH); 37.4(CH.sub.2); 30.9(CH.sub.2); 21.0(CH.sub.2); 35.6(CH.sub.2); 35.40(CH); 27.0(CH.sub.2); 13.6(CH.sub.3); 38.9(CH.sub.2); 19.4(CH.sub.3) Vf R.sub.1,3 = H, 153.0(C); 138.7(C); 135.6(C); 65 ± 10 and 43.0(C); 50.4(CH); 56.3(CH); R.sub.2,4,5 = CH.sub.3 24.5(CH.sub.2); 28.3(CH.sub.2); 68.4(CH); 71.4(CH); 126.1(C); 112.3(CH); 40.0(CH); 40.2(CH.sub.2); 132.6(C); 124.3(CH); 35.8(C); 41.9(CH); 41.1(CH); 37.4(CH.sub.2); 30.9(CH.sub.2); 21.0(CH.sub.2); 35.6(CH.sub.2); 32.3(CH.sub.3); 35.4(CH); 24.5(CH.sub.2); 13.6(CH.sub.3); 16.8(CH.sub.3); 21.6(CH.sub.3); 13.5(CH.sub.3); 39.2(CH.sub.2); 19.4(CH.sub.3); Vg R.sub.1,2,4 = H, 154.7(C); 137.8(C); 135.8(C); 50 ± 10 R.sub.3 = F, 43.0(C); 50.4(CH); 56.3(CH); and 24.5(CH.sub.2); 28.3(CH.sub.2); 156.5(C); R.sub.5 = C.sub.2H.sub.5 68.4(CH); 71.4(CH); 102.3(CH); 116.8(CH); 40.0(CH); 40.2(CH.sub.2); 109.9(CH); 35.8(C); 41.9(CH); 41.1(CH); 37.4(CH.sub.2); 30.9(CH.sub.2); 21.0(CH.sub.2); 35.6(CH.sub.2); 40.4(CH.sub.2); 35.4(CH); 24.8(CH.sub.2); 13.6(CH.sub.3); 39.2(CH.sub.2); 15.1(CH.sub.3); 19.4(CH.sub.3) Vh R.sub.1,4 = H, 141.5(C); 132.0(C); 139.2(C); 55 ± 10 R.sub.3 = I, 43.0(C); 50.4(CH); 56.3(CH); R.sub.2 = OH; 24.5(CH.sub.2); 28.3(CH.sub.2); 78.9(C); and 160.6(C); 68.4(CH); 71.4(CH); R.sub.5 = I 125.7(CH); 104.0(CH); 40.0(CH); 40.2(CH.sub.2); 35.8(C); 41.9(CH); 41.9(CH); 41.1(CH); 37.4(CH.sub.2); 30.9(CH.sub.2); 21.0 (CH.sub.2); 35.6(CH.sub.2); 35.4(CH); 25.5(CH.sub.2); 13.5(CH.sub.3); 38.0(CH.sub.2); 19.4(CH.sub.3)

Example 3. Synthesis of Derivative (VII)

[0050] ##STR00010##

[0051] A mixture of 2.7 g (0.01 mole) of modafinil (VI), 1.08 g (0.01 mole) of ortho-phenylenediamine (II), 5 ml of glacial acetic acid and 3 ml of dimethylformamide was boiled for 90 minutes. The solution was cooled, the precipitate (VII) formed was filtered off and dried and then crystallized from methanol. The yield was 60-65%.

[0052] Instead of unsubstituted (II), its substituted derivatives can be made with R.sub.1-4 as H, CH.sub.3, C.sub.2H.sub.5, Br, Cl, I, F, OH, CN, NO.sub.2, or COOH and with R.sub.5 as H, CH.sub.3, C.sub.2H.sub.5, or I.

[0053] Instead of glacial acetic acid, a mixture of 5 ml of toluene and 5 ml of dimethylformamide can be used. Instead of recrystallization, precipitation from a solution of glacial acetic acid can be used by adding 5 ml of water to the cooled reaction mixture and settling the solution for a day. The precipitate that forms can be filtered off and re-precipitated from glacial acetic acid with water as described above.

[0054] Table 3 below tabulates the analysis data for some of the synthesized Formula 1 Compound Derivatives (VII).

TABLE-US-00003 TABLE 3 Results of NMR .sup.13C Analysis of some of Synthesized Formula 1 Compounds (VII) and Percentage (%) Synthesis Yields Substance % Yield Code Substituents NMR .sup.13C, PPM Theoretical VIIa R.sub.1-5 = H 141.5 (C); 138.9 (C); 115.2 (CH); 63 ± 10 135.2 (CH); 123.1 (CH); 130.0 (CH); 129.2 (CH); 126.2 (CH); 49.8 (CH.sub.2); 67.2 (CH) VIIb R.sub.1-3,5 = H, 141.5 (C); 138.8 (C); 129.5 (C); 67 ± 10 and 117.5 (C); 120.4 (CH); 135.2 (C); R.sub.4 = COOH 125.6 (CH); 122.9 (CH); 130.1 (CH); 129.2 (CH); 126.2 (CH); 49.8 (CH.sub.2) VIIc R.sub.1,3-5 = H, 141.5 (C); 145.0 (C); 144.3 (C); 55 ± 10 and 112.9 (CH); 116.1 (CH); R= NO.sub.2 135.2 (C); 118.6 (CH); 130.1 (CH); 129.2 (CH); 126.2 (CH); 49.8 (CH2) VIId R.sub.1,3-5 = H, 141.5 (C); 138.7 (C); 135.4 (C); 50 ± 10 and 126.1 (C); 112.3 (CH); 132.6 (C); R.sub.2,4 = CH.sub.3 135.2 (C); 124.3 (CH); 130.1 (CH); 129.2 (CH); 126.2 (CH); 49.8 (CH.sub.2) VIIe R.sub.1,3-5 = H, 141.5 (C); 141.7 (C); 136.4 (C); 66 ± 10 and 122.1 (C); 130.6 (C); 113.9 (CH); R.sub.2,4 = Cl 135.2 (C); 123.7 (CH); 130.1 (CH); 129.2 (CH); 126.2 (CH); 49.8 (CH.sub.2); 67.2 (CH); VIIf R.sub.1,3-5 = H, 141.5 (C); 143.3 (C); 140.2 (C); 60 ± 10 and 112.1 (C); 119.7 (C); 117.7 (CH); R.sub.2,4 = Br 135.2 (C); 129.5 (CH); 130.1 (CH); 129.2 (CH); 126.2 (CH); 49.8 (CH.sub.2); 67.2 (CH); VIIg R.sub.1,3 = H, 141.5 (C); 138.7 (C); 135.6 (C); 72 ± 10 and 126.1 (C); 112.3 (CH); 132.6 (C); R.sub.2,4,5 = CH.sub.3 135.2 (C); 124.3 (CH); 130.1 (CH); 129.2 (CH); 126.2 (CH); 47.3 (CH.sub.2); 67.2 (CH); 32.5 (CH.sub.3); 16.8 (CH.sub.3); 21.6 (CH.sub.3); VIIh R.sub.1,2,4 = H, 141.5 (C); 137.8 (C); 135.8 (C); 58 ± 10 R.sub.3 = F, 156.5 (C); 102.4 (CH); 116.8 (CH); and 135.2 (C); 109.9 (CH); 130.1 (CH); R.sub.5 = C.sub.2H.sub.5 129.2 (CH); 126.2 (CH); 47.6 (CH.sub.2); 67.2 (CH); 40.6 (CH.sub.2); 15.1 (CH.sub.3) VIIi R.sub.1,4 = H, 141.5 (C); 132.1 (C); 139.2 (C); 55 ± 10 R.sub.3 = I, 78.9 (C); 160.6 (C); 125.7 (CH); R.sub.2 = OH 104.0 (CH); 135.2 (C); and 109.9 (CH); 130.1 (CH); R.sub.5 = I 129.2 (CH); 126.2 (CH); 48.3 (CH.sub.2); 67.2 (CH)

Example 4. Synthesis of Derivative (IX)

[0055] ##STR00011##

[0056] A mixture of 0.01 mole of amino acid (VIII), 0.01 mole of ortho-phenylenediamine (II), 10 ml of glacial acetic acid was boiled for 60 minutes. The solution was cooled, 7 ml of isopropyl alcohol was added, a day later the precipitate (IX) was filtered off and dried and then was re-precipitated from glacial acetic acid with isopropanol as described above. The yield was 70-85%.

[0057] Instead of unsubstituted (II), its substituted derivatives can be made with R.sub.1-4 as H, CH.sub.3, C.sub.2H.sub.5, Br, Cl, I, F, OH, CN, NO.sub.2, or COOH, and with R.sub.5 as H, CH.sub.3, C.sub.2H.sub.5, or I. The amino acid (VIII) can be selected for example, as an unsubstituted or a substituted derivative of an amino acid such as for example glutamic acid, aspartic acid, arginine, lysine, an amide of glutamic, an amide of aspartic acid, valine, tryptophan, or alanine.

[0058] Instead of glacial acetic acid, a mixture of 5 ml of toluene and 5 ml of dimethylformamide can be used. Instead of recrystallization, precipitation from a solution of glacial acetic acid can be used by adding 5 ml of water to the cooled reaction mixture and settling the solution for a day. The precipitate that forms can be filtered off and reprecipitated from glacial acetic acid with water as described above. Table 4 below tabulates the analysis data for some of the synthesized Formula I Compounds (IX).

TABLE-US-00004 TABLE 4 Results of NMR .sup.13C Analysis of some of Synthesized Formula I Compounds (IX) and Percentage (%) Synthesis Yields Substance % Yield Code Substituents NMR .sup.13C, PPM Theoretical IXa R.sub.1-5,13,14 = H, and   [00012] 141.5 (C); 138.9 (C); 115.2 (CH); 123.0 (CH); 158.0 (CH); 55.1 (CH); 41.9 (CH); 36.5 (CH); 24.8 (CH.sub.2) 65 ± 10 IXb R.sub.1-5,13,14 = H, and   [00013] 141.5 (C); 138.9 (C); 115.2 (CH); 123.0 (CH); 158.0 (CH); 55.1 (CH); 42.0 (CH); 36.5 (CH); 27.2 (CH.sub.2) 60 ± 10 IXc R.sub.1-5,13,14 = H, and   [00014] 141.5 (C); 138.9 (C); 136.5 (CH); 123.0 (CH); 127.4 (C); 110.8 (C); 115.2 (CH); 111.2 (CH); 118.8 (CH); 123.0 (CH); 121.7 (CH); 119.8 (CH); 58.6 (CH); 37.8 (CH.sub.2) 75 ± 10 IXd R.sub.1-5,13,14 = H, and   [00015] 141.5 (C); 138.9 (C); 115.2 (CH); 123.0 (CH); 178.4 (C); 54.8 (CH); 30.6 (CH); 33.0 (CH.sub.2) 79 ± 10 IXe R.sub.1-5,13,14 = H, and   [00016] 141.5 (C); 138.9 (C); 115.2 (CH); 123.0 (CH); 172.1 (C); 50.2 (CH); 44.8 (CH.sub.2) 66 ± 10 IXf R.sub.1-5,13,14 = H, and   [00017] 141.5 (C); 138.9 (C); 115.2 (CH); 123.0 (CH); 174.3 (C); 50.8 (CH); 46.4 (CH.sub.2) 80 ± 10 IXg R.sub.1-5,13,14 = H, and   [00018] 141.5 (C); 138.9 (C); 115.2 (CH); 123.0 (CH); 74.3 (CH.sub.2); 55.4 (CH); 21.6 (CH.sub.2); 35.4 (CH.sub.2) 75 ± 10

Example 5. Synthesis of Derivative (XI)

[0059] ##STR00019##

[0060] A mixture of 0.01 mole of pangamic acid (X), 0.01 mole of ortho-phenylenediamine (II), 10 ml of glacial acetic acid was boiled for 30 minutes. The solution was cooled, 5 ml of isopropyl alcohol was added, a day later the precipitate (XI) was filtered off and dried, and then was re-precipitated from glacial acetic acid with isopropanol as described above. The yield was 60-75%.

[0061] Instead of unsubstituted (II), its substituted derivatives can be made with R.sub.1-4 as H, CH.sub.3, C.sub.2H.sub.5, Br, Cl, I, F, OH, CN, NO.sub.2, or COOH, and with R.sub.5 as H, CH.sub.3, C.sub.2H.sub.5, or I. Instead of pangamic acid (X), alternatively, biotin, pantothenic acid, folic acid, cyanocobalamin can be used.

[0062] Instead of glacial acetic acid, a mixture of 5 ml of toluene and 5 ml of dimethylformamide can be used. To purify the product, precipitation from a solution of glacial acetic acid can be used by adding 5 ml of water to the cooled reaction mixture and settling the solution for a day. The precipitate that formed is filtered off and reprecipitated from glacial acetic acid with water as described above. Table 5 below tabulates the analysis data for some of the synthesized Formula I Compounds (XI).

TABLE-US-00005 TABLE 5 Results of NMR .sup.13C Analysis of some of Synthesized Formula 1 Compounds (XI) and Percentage (%) Synthesis Yields Sub- % Yield stance Theo- Code Substituents NMR .sup.13C, PPM retical XIa R.sub.1-5 = H 141.5 (C); 138.9 (C); 115.2 (CH); 63 ± 10 123.1 (CH); 171.2 (C); 66.9 (CH); 70.3 (CH); 69.1 (CH); 69.3 (CH); 65.0 (CH.sub.2); 47.2 (CH.sub.2); 53.9 (CH.sub.3) XIb R.sub.1-3,5 = H, 141.5 (C); 138.8 (C); 117.5 (C); 60 ± 10 and 120.4 (CH); 125.6 (CH); R.sub.4 = COOH 122.9 (CH); 166.4 (C); 171.2 (C); 66.9 (CH); 70.3 (CH); 69.1 (CH); 69.3 (CH); 65.0 (CH.sub.2); 47.2 (CH.sub.2); 53.9 (CH.sub.3) XIc R.sub.1,3-5 = H, 141.5 (C); 139.8 (C); 133.7 (C); 75 ± 10 and 137.0 (C); 121.3 (CH); 118.6 (CH); R.sub.2 = NO.sub.2 123.9 (CH); 171.2 (C); 66.9 (CH); 70.3 (CH); 69.1 (CH); 69.3 (CH); 65.0 (CH.sub.2); 47.2 (CH.sub.2); 53.9 (CH.sub.3) XId R.sub.1,3,5 = H, 141.5 (C); 138.7 (C); 135.4 (C); 50 ± 10 and 126.1 (C); 112.3 (CH); 132.6 (C); R.sub.2,4 = —CH.sub.3 124.3 (CH); 171.2 (C); 66.9 (CH); 70.3 (CH); 69.1 (CH); 69.3 (CH); 65.0 (CH.sub.2); 47.2 (CH.sub.2); 53.9 (CH.sub.3); 16.5 (CH.sub.3); 21.6 (CH.sub.3) XIe R.sub.1,3,5 = H, 141.5 (C); 141.7 (C); 136.4 (C); 66 ± 10 and 122.1 (C); 130.6 (C); 113.9 (CH); R.sub.2,4 = Cl 135.2 (C); 123.7 (CH); 130.1 (CH); 129.2 (CH); 126.2 (CH); 49.8 (CH.sub.2); 67.2 (CH); XIf R.sub.1,3,5 = H, 141.5 (C); 143.3 (C); 140.2 (C); 60 ± 10 and 112.1 (C); 119.7 (C); 117.7 (CH); R.sub.2,4 = Br 135.2 (C); 129.5 (CH); 130.1 (CH); 129.2 (CH); 126.2 (CH); 49.8 (CH.sub.2); 67.2 (CH); XIg R.sub.1,3 = H, 141.5 (C); 138.7 (C); 135.6 (C); 72 ± 10 and 126.1 (C); 112.3 (CH); 132.6 (C); R.sub.2,4,5 = CH.sub.3 135.2 (C); 124.3 (CH); 130.1 (CH); 129.2 (CH); 126.2 (CH); 47.3 (CH.sub.2); 67.2 (CH); 32.5 (CH.sub.3); 16.8 (CH.sub.3); 21.6 (CH.sub.3); XIh R.sub.1,2,4 = H, 141.5 (C); 137.8 (C); 135.8 (C); 58 ± 10 R.sub.3 = F, 156.5 (C); 102.4 (CH); 116.8 (CH); and 135.2 (C); 109.9 (CH); 130.1 (CH); R.sub.5 = C.sub.2H.sub.5 129.2 (CH); 126.2 (CH); 47.6 (CH.sub.2); 67.2 (CH); 40.6 (CH.sub.2); 15.1 (CH.sub.3) XIi R.sub.1,4 = H, 141.5 (C); 132.1 (C); 139.2 (C); 55 ± 10 R.sub.3 = I, 78.9 (C); 160.6 (C); 125.7 (CH); R.sub.2 = OH, 104.0 (CH); 135.2 (C); 109.9 (CH); and 130.1 (CH); 129.2 (CH); R.sub.5 = I 126.2 (CH); 48.3 (CH.sub.2); 67.2 (CH)

Example 6. Synthesis of Derivative (XIII)

[0063] ##STR00020##

[0064] A mixture of 0.01 mole of orotic acid (XII), 0.01 mole of ortho-phenylenediamine (II), 10 ml of glacial acetic acid was boiled for 90 minutes. The solution was cooled, 5 ml of isopropyl alcohol was added, after a day the precipitate (XIII) was filtered off and dried, and then was re-precipitated from glacial acetic acid with isopropanol as described above. The yield was 65-75%.

[0065] Instead of unsubstituted (II), its substituted derivatives can be made with R.sub.1-4 as H, CH.sub.3, C.sub.2H.sub.5, Br, Cl, I, F, OH, CN, NO.sub.2, or COOH, and with R.sub.5 as H, CH.sub.3, C.sub.2H.sub.5, or I.

[0066] Instead of glacial acetic acid, a mixture of 5 ml of toluene and 5 ml of dimethylformamide can be used. To purify the product, precipitation from a solution of glacial acetic acid can be used by adding 5 ml of water to the cooled reaction mixture and settling the solution for a day. The precipitate that formed is filtered off and reprecipitated from glacial acetic acid with water as described above. Table 6 below tabulates the analysis data of some of the synthesized Formula I Compounds (XIII).

TABLE-US-00006 TABLE 5 Results of NMR .sup.13C Analysis of some of Synthesized Formula 1 Compounds (XIII) and Percentage (%) Synthesis Yields Substance % Yield Code Substituents NMR .sup.13C, PPM Theoretical XIIIa R.sub.1-5 = H 141.5 (C); 138.9 (C); 65 ± 10 150.7 (CH); 163.5 (CH); 154.7 (CH); 115.2 (CH); 95.3 (CH); 123.0 (CH) XIIIb R.sub.1-3,5 = H, 141.5 (C); 138.8 (C); 75 ± 10 and 129.5 (C); 150.7 (C); R.sub.4 = COOH 163.5 (C); 154.7 (C); 117.5 (C); 120.4 (CH); 95.3 (CH); 125.6 (CH); 122.9 (CH); 166.4 (C) XIIIc R.sub.1,3-5 = H, 141.5 (C); 139.8 (C); 75 ± 10 and 133.7 (C); 150.7 (C); R.sub.2 = NO.sub.2 163.5 (C); 154.7 (C); 137.0 (C); 121.3 (CH); 95.3 (CH); 118.6 (CH); 123.9 (CH) XIIId R.sub.1,3,5 = H, 141.5 (C); 138.7 (C); 80 ± 10 and 135.4 (C); 150.7 (C); R.sub.2,4 = CH.sub.3 163.5 (C); 154.7 (C); 126.1 (C); 112.3 (CH); 132.6 (C); 95.3 (CH); 124.3 (CH); 16.5 (CH.sub.3); 21.6 (CH.sub.3) XIIIe R.sub.1,3,5 = H, 141.5 (C); 141.7 (C); 78 ± 10 and 136.4 (C); 122.1 (C); R.sub.2,4 = Cl 130.6 (C); 150.7 (C); 163.5 (C); 154.7 (CH); 113.9 (CH); 123.7 (CH); 95.3 (CH) XIIIf R.sub.1,3,5 = H, 141.5 (C); 143.3 (C); 60 ± 10 and 140.2 (C); 112.1 (C); R.sub.2,4 = Br 119.7 (C); 150.7 (CH); 163.5 (C); 154.7 (CH); 117.7 (CH); 129.2 (CH); 95.3 (CH) XIIIg R.sub.1,3 = H, 141.5 (C); 138.7 (C); 80 ± 10 and 135.6 (C); 150.7 (C); R.sub.2,4,5 = CH.sub.3 163.5 (C); 154.7 (C); 126.1 (C); 112.3 (CH); 132.6 (CH); 95.3 (CH); 124.3 (CH); 34.4 (CH.sub.3); 16.8 (CH.sub.3); 21.6 (CH.sub.3); XIIIh R.sub.1,2,4 = H, 141.5 (C); 134.5 (C); 58 ± 10 R.sub.3 = F, 135.8 (C); 156.5 (C); and 150.7 (CH); 163.5 (CH); R.sub.5 = C.sub.2H.sub.5 154.7 (C); 102.4 (CH); 116.8 (CH); 95.3 (CH); 109.9 (CH) ;40.5 (CH.sub.2); 15.2 (CH.sub.3) XIIIi R.sub.1,4 = H, 141.5 (C); 132.1 (C); 55 ± 10 R.sub.3 = I, 139.2 (C); 78.9 (C); R.sub.2 = OH, and 150.7 (C); 163.5 (CH); R.sub.5 = I 160.6 (CH); 154.7 (C); 125.7 (CH); 104.0 (CH); 95.3 (CH)

Example 7. Synthesis of Derivative (XIV)

[0067] ##STR00021##

[0068] A mixture of 0.01 mole of acridoneacetic acid (XIV), 0.01 mole of ortho-phenylenediamine (II), 10 ml of glacial acetic acid was boiled for 90 minutes. The solution was cooled, 5 ml of isopropyl alcohol was added, after a day the precipitate (XV) was filtered off and dried, and then re-precipitated from glacial acetic acid with isopropanol as described above. The yield was 55-60%.

[0069] Instead of unsubstituted (II), its substituted derivatives can be made with R.sub.1-4 as H, CH.sub.3, C.sub.2H.sub.5, Br, Cl, I, F, OH, CN, NO.sub.2, or CO H, and with R.sub.5 as H, CH.sub.3, C.sub.2H.sub.5, or I.

[0070] Instead of glacial acetic acid, a mixture of 5 ml of toluene and 5 ml of dimethylformamide can be used. To purify the product, precipitation from a solution of glacial acetic acid can be used by adding 5 ml of water to the cooled reaction mixture and settling the solution for a day. The precipitate that formed is filtered off and reprecipitated from glacial acetic acid with water as described above. Table 7 below tabulates the analysis data of some of the synthesized Formula I Compounds (XV).

TABLE-US-00007 TABLE 7 Results of NMR .sup.13C Analysis of some of Synthesized Formula 1 Compounds (XV) and Percentage (%) Synthesis Yields Substance % Yield Code Substituents NMR .sup.13C, PPM Theoretical XVa R.sub.1-5 = H 141.5 (C); 138.9 (C); 175.7 (C); 57 ± 3  144.4 (C); 115.2 (CH); 121.7 (C); 116.2 (CH); 123.0 (CH); 126.5 (CH); 133.3 (CH); 121.5 (CH); 61.4 (CH.sub.2) XVb R.sub.1-3,5 = H, 141.5 (C); 138.9 (C); 129.5 (C); 52 ± 10 and 175.7 (C); 144.4 (C); 117.5 (CH); R.sub.4 = COOH 120.4 (CH); 121.7 (C); 116.2 (CH); 125.6 (CH); 122.9 (CH); 126.5 (CH); 133.3 (CH); 121.5 (CH); 166.4 (C); 61.4 (CH.sub.2) XVc R.sub.1,3-5 = H, 141.5 (C); 142.5 (C); 145.0 (C); 55 ± 5  and 144.4 (C); 112.9 (CH); 121.7 (C); R.sub.2 = NO.sub.2 116.1 (CH); 121.7 (C); 116.2 (CH); 118.6 (CH); 126.5 (CH); 133.3 (CH); 121.5 (CH); 61.4 (CH.sub.2) XVd R.sub.1,3,5 = H, 141.5 (C); 141.7 (C); 136.4 (C); 60 ± 10 and 122.1 (C); 130.6 (C); 175.7 (C); R.sub.2,4 = CH.sub.3 144.4 (C); 113.9 (CH); 121.7 (C); 123.7 (CH); 116.2 (CH); 126.5 (CH); 133.3 (CH); 121.5 (CH); 61.4 (CH.sub.2) XVe R.sub.1,3,5 = H, 141.5 (C); 141.7 (C); 136.4 (C); 70 ± 10 and 122.1 (C); 130.6 (C); 150.7 (C); R.sub.2,4 = Cl 163.5 (C); 154.7 (CH); 113.9 (CH); 123.7 (CH); 95.3 (CH) XVf R.sub.1,3,5 = H, 141.5 (C); 143.3 (C); 140.2 (C); 55 ± 10 and 112.2 (C); 119.7 (C); 175.7 (C); R.sub.2,4 = Br 144.4 (C); 117.7 (CH); 121.7 (C); 129.5 (CH); 116.2 (CH); 126.5 (CH); 133.3 (CH); 121.5 (CH); 61.4 (CH.sub.2) XVg R.sub.1,3 = H, 148.1 (C); 138.7 (C); 135.6 (C); 65 ± 10 and 175.7 (C); 144.4 (C); 126.1 (C); R.sub.2,4,5 = CH.sub.3 112.3 (CH.sub.3); 121.7 (C); 132.6 (CH); 116.2 (CH); 124.3 (CH); 126.5 (CH); 133.3 (CH); 121.5 (CH); 32.0 (CH.sub.3); 16.8 (CH.sub.3); 21.6 (CH.sub.3); 58.9 (CH.sub.2) XVh R.sub.1,2,4 = H, 148.1 (C); 137.8 (C); 135.8 (C); 55 ± 10 R.sub.3 = F, 156.54 (C); 175.7 (C); 144.4 (C); and 102.4 (CH); 116.8 (CH); 121.7 (C); R.sub.5 = C.sub.2H.sub.5 116.2 (CH); 109.9 (CH); 126.5 (CH); 116.3 (CH); 126.5 (CH); 133.3 (CH); 121.5 (CH); 40.0 (CH.sub.2); 59.2 (CH.sub.2); 15.1 (CH.sub.3) XVi R.sub.1,4 = H, 141.5 (C); 132.1 (C); 139.2 (C); 50 ± 10 R.sub.3 = I, 78.9 (C); 175.7 (C); 160.6 (C); R.sub.2 = OH, 144.4 (C); 125.7 (CH); 104.0 (CH); and 121.7 (C); 116.2 (CH); R.sub.5 = I 126.5 (CH); 116.2 (CH); 126.5 (CH); 133.3 (CH); 121.5 (CH); 59.9 (CH.sub.2)

Example 8: Geroprotective Activity of the Synthesized Formula I Compounds

[0071] An important effect of imidazoline receptor activators is a geroprotective effect (an increase in the lifespan of animals). For the present invention the term animal shall mean any kind of animal, such as a pet, a human, a patient, a living subject, or a person.

[0072] One well-studied animal-lifespan model for the inventors has been the survival model of the insect Drosophila (fruit fly) due to their relatively short lifespan. Drosophila melanogaster lines were selected for their differences in reproductive function. The genetic selection of related Drosophila lines was been carried out for reproductive function (sexual activity of males). The genetic selection was accomplished by close inbreeding with individual crosses in each generation of full brothers and sisters. Using this process of genetic selection, a series of fruit fly lines differing in breeding characteristics (BA−, HA−, HA+) were repeatedly obtained by a method of return genetic selection. This selection process led to an acquisition of low-level fruit fly lines with a complex number of genetically-controlled changes. The most interesting genetically-controlled changes affected the neuroendocrine system of the flies and this became the subject of special studies by the inventors. In the Drosophila lines laid down from the natural population of “GL”, the genetic selection was carried out to select for fruit fly embryonic mortality accompanied by close inbreeding.

[0073] As a result of the special studies, two contrasting inbred lines were obtained for further study. The two contrasting inbred lines are: (1) a high (HEM line) and (2) a low embryonic mortality (LEM line). At the same time, a sample of flies from the natural population of the GL was maintained as a Control fruit flies group without any genetic selection in mass fruit fly crops. It was found that the fruit fly lines of HEM and GL are characterized by having a threefold difference in their number of viable offspring, while not differing in fertility which was determined by the number of laid eggs per unit of time. In the HEM line, 81% of fruit fly eggs stopped developing at early stages of ontogenesis. The HEM line was found to have a high frequency of an early dominant lethal (EDL) mortality which increased from 65% on the first day of fruit fly egg laying to 95% on the fourth day of the fruit fly egg laying. No differences were found between the two studied lines in terms of late dominant lethality. Further genetic analysis determined that the frequency and the dynamics of the occurrence of early dominant lethal (EDL) in the high embryonic mortality (HEM) fruit fly line was only determined by the genotype of the female flies. In addition, a system of balanced lethal mutations arose in the HEM line by the 86th generation of directed selection which was found to create a permanent heterozygosity on a small section of the second chromosome of the fruit flies.

Terminology Related to the Present Invention

[0074] Antigeriatric action is an action which includes pharmacological effects aimed at prolonging the life of a living organism: these drugs include histone deacetylase inhibitors, phosphodiesterase inhibitors, type I.sub.1 and I.sub.2 imidazoline receptor stimulants, activators of telomerase expression, immunomodulators, antiviral agents, anticancer agents, statins, and antihyperglycemic drugs (metformin). A common generic feature of this pharmacological action is ae physical extension of human or animal life.

[0075] Telomerase is an enzyme that adds specific repeating DNA sequences (TTAGGG in vertebrates) to the 3′-end of the DNA strand in telomere regions that are located at the ends of chromosomes in eukaryotic cells. Telomeres contain condensed DNA and stabilize chromosomes. With each cell division, the telomeric regions are shortened. The existence of a mechanism that compensates for the shortening of telomeres (telomerase) was predicted in 1973 by A. M. Olovnikov. Telomerase is a reverse transcriptase, and a special RNA molecule is associated with it, which is used as a template for reverse transcription during telomere elongation.

[0076] As a result of the telomerase activity, the length of telomeric regions of the cell's chromosomes increases or remains at a constant level, thus compensating for terminal under replication and allowing the cell to divide for an unlimited time. In the course of the study of this enzyme (consisting, as described below, of the RNA component and the protein component), it was found that the RNA component is expressed at a constant level in almost all cells, and the expression of the protein component is required to induce telomerase activity, which is therefore called the catalytic component of telomerase.

[0077] Artificially induced expression of the gene for the catalytic component of telomerase (by introducing the gene using genetic engineering methods) makes the cell culture immortal, that is, capable of dividing indefinitely, thereby canceling the Hayflick limit for culture. Telomerase is expressed in stem, sex, and some other types of cells in the body, which must constantly divide for the functioning of certain tissues (for example, intestinal epithelial cells). Ordinary somatic cells of the body are devoid of telomerase activity. Cells of 85% of cancerous tumors have telomerase activity; therefore, telomerase activation is considered to be one of the activator factors of the cell leading to a malignant transformation of a cancer cell.

Geroprotective Test of Formula 1 Compounds:

[0078] The initial number of fruit fly adults during the first six hours after emergence was subjected to ether anesthesia and placed in individual glass cups (from 5 to 10 virgin females and males in each). The cultures were assigned individual numbers. Subsequently, the dead individuals were regularly counted visually in each glass separately, without ether anesthesia, after which the surviving flies were transferred to a fresh medium, while maintaining the serial number of the glass. The size of each fruit flies cohort ranged in number from between about 100 to about 500 individuals.

[0079] The age and percent living fruit flies data were used with the below Survival Curve Equation: Y=100/(1+EXP.sub.10((MT.sub.50−X)×HS)) wherein X is the age of the Fruit Flies cohort, and wherein Y is the percentage of living individuals in the Fruit Flies cohort. For each drug compound tested on these fruit flies, the experimental data was fit by a regression of the Survival Curve Equation to obtain a best MT.sub.50 value and a best HS value. The MT.sub.50 parameter is a close analogue to the average life expectancy. Thus, hereinafter the inventors treat the MT50 value to be the same as the Median Life Span (MLS) of the fruit flies in each experiment. Because the MT.sub.50 was calculated using the least squares regression method, the MT.sub.50 is also the standard regression coefficient, and such coefficients can be compared using a Fisher's “F-test” statistics test. The coefficients of determination for the regression model in all cases was greater than 90%.

[0080] The HS parameter is a calculated slope for experimental data fit to the survival curve equation. Thus HS parameter is analogous to the slope calculated by the Hill Equation. The HS as it is used by the inventors is an indirect estimator of the maximum life span (MLS). The Survivor Curve Equation value for Y asymptotically approached zero with the increasing age of the fruit flies cohort. The inventors elected to define the Expected Maximum Life Duration (EMLD) to be the X axis value when the value of Y (Y being the proportion of living fruit fly individuals) was 0.1%.

[0081] Below Table 8 tabulates the MLS (median life span for the tested synthetic Benzimidazole Formula I compounds which were introduced into the Fruit Flies feed as a 1% solution spray.

TABLE-US-00008 TABLE 8 Median life span for the tested synthetic Benzimidazole Formula 1 compounds which were introduced into the Fruit Flies feed as a 1% solution spray Females Males MLS EMLD MLS EMLD Substance (day) (day) (day) (day) Control 26 ± 2 30.0 21 ± 1 23.0 IIIa 35 ± 5 33 ± 5 IIIb 44 ± 5 42 ± 6 IIIc 32 ± 6 30 ± 5 IId 37 ± 5 39 ± 6 IIIe 38 ± 5 36 ± 5 IIIf 32 ± 5 30 ± 5 IIIg 30 ± 5 30 ± 5 IIIh 52 ± 5 57 ± 5 IIIi 42 ± 6 42 ± 6 Va 40 ± 5 44 ± 6 Vb 33 ± 5 37 ± 5 Vc 37 ± 5 35 ± 5 Vd 43 ± 6 42 ± 6 Ve 40 ± 5 38 ± 5 Vf 43 ± 5 42 ± 6 Vg 44 ± 6 40 ± 6 Vh 43 ± 5 44 ± 6 Vi 32 ± 5 31 ± 5 VIIa 37 ± 5 34 ± 5 VIIb 38 ± 5 33 ± 5 VIIc 35 ± 5 38 ± 5 VIId 33 ± 5 37 ± 5 VIIe 30 ± 5 33 ± 5 VIIf 36 ± 5 37 ± 5 VIIg 33 ± 5 39 ± 5 VIIh 39 ± 5 43 ± 6 VIIi 42 ± 6 48 ± 7 IXa 54 ± 8 59 ± 8 IXb 55 ± 6 57 ± 8 IXc 34 ± 5 42 ± 5 IXd 37 ± 5 36 ± 5 IXe 35 ± 5 38 ± 5 IXf 22 ± 5 26 ± 5 IXg 43 ± 6 44 ± 6 XIa 50 ± 7 57 ± 7 XIb 43 ± 6 44 ± 6 XIe 40 ± 6 42 ± 6 XId 33 ± 5 35 ± 5 XIe 36 ± 5 38 ± 5 XIf 37 ± 5 36 ± 5 XIg 35 ± 5 39 ± 5 XIh 40 ± 6 44 ± 6 XIi 47 ± 6 48 ± 7 XIIIa 40 ± 6 38 ± 5 XIIIb 35 ± 5 35 ± 5 XIIIc 55 ± 7 59 ± 7 XIIId 44 ± 6 45 ± 6 XIIIe 40 ± 5 39 ± 5 XIIIf 45 ± 6 45 ± 6 XIIIg 32 ± 5 33 ± 5 XIIIh 54 ± 8 59 ± 8 XIIIi 43 ± 6 45 ± 6 XVa 49 ± 7 55 ± 9 XVb 47 ± 6 48 ± 7 XVc 45 ± 6 43 ± 6 XVd 49 ± 8 48 ± 7 XVe 44 ± 6 46 ± 5 XVf 40 ± 5 42 ± 6 XVg 67 ± 9 66 ± 9 XVh 55 ± 8 54 ± 8 XVi 50 ± 8 55 ± 7

[0082] The experimental data shows that nearly all of the tested benzimidazole derivatives prolonged the life of the fruit flies. Some of the tested benzimidazole derivative compounds were surprisingly more effective in providing a geroprotection (an anti-geriatric action) for the Drosophila fruit flies, based on the criteria of extending the MLS of the flies by up to between 3 to 4 fold. Preferred compounds of the invention are synthetic Benzimidazole Formula I compounds Nos. IIIh, IXa, IXb, Xia, XIIIh, XVa, XVg, XVh, and XVi. These preferred compounds extended the median life span (MLS) of the fruit flies up to 50 days or more whereas the MLS of the control (normal) fruit flies was 21-26 days. A more preferred compound is the synthetic Benzimidazole Formula I compound No. XVg which extended the lifespan of Drosophila by nearly 3 fold to 70 days. The chemical structure for Compound No. XVg is drawn and named below.

##STR00022##