MXPA97009275A - Use of derivatives of sulfamic acid, acil sulfonamides or sulfonil carbamates for the manufacture of a medicinal product to reduce delipoprotei levels - Google Patents

Abstract

The present invention relates to: It leads to new therapeutic uses of the compounds of Formula (I) wherein X and Y are oxygen, sulfur or (CR'R ") n where n is 1 to 4, R is hydrogen, alkyl or benzyl; R1 and R2 are phenyl, substituted phenyl, naphthyl, substituted naphthyl, an aralkyl group, an alkyl, adamantyl or a cycloalkyl group. The uses are for cerebrovascular diseases such as attacks, peripheral vascular diseases and restenos

Description

USE OF DERIVATIVES OF SULPHAMIC ACID, ACIL SULFONAMIDES OR SULFONIL CARBAMATES FOR THE MANUFACTURE OF A MEDICATION TO DECREASE LEVELS OF LIPOPROTEINS BACKGROUND OF THE INVENTION The compounds of the present invention are described fully in the Copending application of the United States with serial number 08 / 223,932 filed on April 13, 1994. The use of the compounds shown is hypercholesterolemia and atherosclerosis. This application is incorporated herein by reference.

The compounds of the copending application increased chemical stability over those of U.S. Patent No. 5, 254,068.

The present invention relates generally to lipoprotein (a), Lp (a) and more particularly to the methods and agents for lowering its plasma concentrations to achieve a therapeutic benefit.

The macromolecule known as lipoprotein (a), or Lp (a), is a low density lipoprotein (LDL) complex and a hydrophilic glycoprotein that has been given the name of apoliprotein (a), or apo (a). The main LDL protein is apo B-l 00 and apo (a) binds to the apo B half of LDL via a sulfide bond. LDL is the largest cholesterol transporter in human plasma. The physiological function of Lp (a) is unknown.

Apo (a) is not structurally similar to other apolipoproteins, but exhibits similarity to another plasma protein called plasminogen. The structure of the plasminogen includes five homologous domains repeated together called kringles (Kringles I - V) which are pretzel-like structures stabilized by three internal disulfide bridges followed by a protease domain. Kringle structures have been identified in several other proteins such as prothrombin, tissue-type plasminogen activator (t -PA), urokinase and coagulation factor XII (Utermann, Science, 1989; 246: 904-910).

Apo (a) lacks similar Kringles from I to III of the plasminogen, but has multiple copies of the Kringle domain similar to the plasminogen quarter and a single copy of a Kringle domain similar to the fifth of plasminogen (Kringle-5). Apo (a) also contains a protease domain.

Lp (a) was first identified by Berg in 1963 (Berg, Acta Pathol, Microbiol Scand., 1963; 59: 369) as an antigenic activity associated with the LDL fraction in the plasma of some individuals. Plasma Lp (a) levels vary in different individuals from less than 2 mg / dL to more than 200 mg / dL. Increased plasma levels of Lp (a) are considered to be a risk factor for atherosclerosis, either alone or in combination with elevated LDL levels (Kostner, et al., Circulation, 1989; 80 (5): 1313- 1319 citing previous researchers). The concentration of Lp (a) in the plasma and the size of Apo (a) are determined genetically (Gavish, et al., J. Clin Invest., 1989; 84: 2021-2027).

The discovery of the homology of apo (a) to plasminogen, has led to further investigations as the role played by Lp (a). Hajjar, et al., Nature, 1989; 339: 303-305 considers the similarity between the apo (a) component of Lp (a) and plasminogen and investigates the effect that Lp (a) could have on the interaction between plasminogen and the endothelial cell and found that Lp (a) ) competes for plasminogen binding sites and appears to be able to inhibit the activation of plasminogens on the surface of endothelial cells by t - PA. This suggests that high levels of Lp (a) could impair and inhibit fibrinolysis of the cell surface, interfering in this way with the fibrinolytic system. In Kostner, et al., (See above), the HMG-CoA reductase inhibitors such as simvastatin and lovastatin, as well as other known cholesterol lowering agents are administered to a group of test patients and then, the samples of plasma are taken and examined. Most of the tested agents failed at lower levels of Lp (a) and, in fact, in some cases, Lp (a) levels appear to increase, possibly due to the stimulation of Lp (a) production. The authors identified only two agents, namely, neomycin and niacin, which lower LDL and Lp levels (to). These agents only diminish Lp (a) to a limit to such a degree and due to this, as well as to the lateral toxic effects, it does not seem to present a viable therapeutic avenue.

Therefore, there is a need for an effective method and associated agents to decrease the levels of Lp (a) in the plasma.

The role of lipoprotein (a) has been studied in patients suffering from ischemic cerebrovascular disease and it has been determined that they have significantly higher levels of lipoprotein (a), lipid transporters by intermediate density proteins, low protein cholesterol density and lower levels of high density lipoproteins than the control subjects. These are, then, factors of greater risk for ischemic cerebrovascular disease (Pedro-Botck, Stroke, 1992; 23 (11): 1556-1562).

Lipoprotein (a) is a genetic risk factor, independent and critical for ischemic attack, especially in young adults (Nagayama, Stroke, 1994; 25 (1): 74-78).

High levels of lipoprotein (a) in serum are an independent risk factor in the development of cerebral infarction (Shintani, Stroke, 1993; 24 (7): 965-969.

Elevated levels of lipoprotein Lp (a) in plasma have been linked to the development of premature atherosclerosis in the coronary circulation (Valentine, Arch. Intern. Med., 1994; 154: 801-806).

The prevention of restenosis after percutaneous transluminal coronary angioplasty by reducing lipoprotein (a) levels with low density lipoprotein apheresis is reported in Daida, Am. J. Card. 1994; 73 (15): 1037-1040.

Lp (a) of serum is an independent factor associated with stenosis of saphenous vein grafts (Hoff, Circulation, 1988; 77 (6): 1238-1243.

SUMMARY OF THE INVENTION The present invention is directed to new uses of compounds I below. The compounds are those of the formula: O O I I R, - X - S - N - C - Y - R2 | | ORI or a pharmaceutically acceptable salt thereof where: X and Y are selected from oxygen, sulfur and (CR'R ") n, where n is an integer from 1 to 4 and R 'and R" are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, optionally substituted phenyl or R 'and R "together form a spirocycloalkyl or a carbonyl, with the proviso that at least one of the X and Y is - (CR' R ") n - and with the additional condition when X and Y are both (CR'R" n and R 'and R "are hydrogen and n is one, R! and R2 are aryl; R is hydrogen, a linear or branched alkyl of 1; to 8 carbon atoms or benzyl; Ri and R2 are each independently selected from: (a) phenyl or phenoxy, each of which is unsubstituted or substituted with 1 to 5 substituents selected from; phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched, an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p is zero or one and each of R3 and R4 is selected from hydrogen or a linear or branched alkyl group having from 1 to 4 carbon atoms; (b) 1 - or 2-naphthyl unsubstituted or substituted with 1 to 3 substituents selected from: phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched; an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; hydroxy, phenoxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p, R3 and R4 have the meaning defined above; (c) arylalkyl; (d) a linear or branched alkyl chain having 1 to 20 carbon atoms and which is saturated or contains 1 to 3 double bonds; or (e) adamantyl or a cycloalkyl group wherein the cycloalkyl moiety has from 3 to 6 carbon atoms; with the following conditions: (i) where X is (CH2) n, Y is oxygen and R1 is a substituted phenyl, then R2 is a substituted phenyl; (ii) where Y is oxygen, X is (CH2) n, R2 is phenyl or naphthyl, then Rj is not a straight or branched alkyl chain; and (iii) the following compounds are excluded: The preferred compounds of the present invention are those of Formula I: wherein Ri is phenyl or is phenyl bisubstituted at positions 2, 6, where R2 is phenyl or phenyl bisubstituted at positions 2, 6, where each of Rj and R2 is phenyl, where each phenyl is bisubstituted at position 2, 6, where Rt is phenyl substituted at positions 2, 6 and R2 is phenyl trisubstituted at positions 2, 4, 6, where Ri is 2, 6-bis (1 - methylethyl) phenyl and R2 is 2,6-bis (1-methylethyl) phenyl or 2,4,6-tris (1-methyl-ethyl) phenyl, where one of Rt and R2 is the group - (CH2) t -> C5- (CH2) W - R7 I Ro where t is zero or 1 to 4; is zero or 1 to 4 with the proviso that the sum of t and w is not greater than 5; R5 and R1 are each independently selected from hydrogen or alkyl having from 1 to 6 carbon atoms or when R5 is hydrogen, R1 can be selected from the groups defined by R7; and R7 is phenyl or phenyl substituted with 1 to 3 substituents selected from a linear or branched alkyl group having 1 to 6 carbon atoms, straight or branched alkoxy group having 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine , chlorine, bromine, nitro, trifluoromethyl, -COOH, COOalkyl wherein P, R3 and R4 have the meaning defined above.

Also the preferred compounds of the present invention are those of the formula I wherein X is oxygen, sulfur or (CR'R ") n; Y is oxygen, sulfur or (CR'R") n; with the proviso that at least one of the X or Y is (CR'R ") n where n is an integer from 1 to 4 and R 'and R" are each independently hydrogen, linear or branched alkyl of 1 to 6 carbon atoms, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R 'and R "together form a carbonyl group or a spirocycloalkyl of 3 to 10 carbons, R is hydrogen, R is phenyl optionally substituted linear or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms; R2 is optionally substituted phenyl, linear or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenoxy optionally substituted with the proviso that only if X is (CR'R ") n Rr can be optionally replaced and only if Y is (CR'R ") n R2 can optionally be substituted phenoxy and with the additional proviso that at least one of R1 and R2 are phenyl or phenoxy optionally substituted.

The most preferred compounds of the present invention are those of the formula I wherein: X is oxygen; Y is (CR'R ") n where n is an integer from 1 to 2, R is hydrogen, R1 is optionally substituted phenyl, R2 is optionally substituted phenyl or phenoxy, linear or branched alkyl of 1 to 10 carbons or 3-cycloalkyl. at 10 carbons, and R 'and R "are each independently hydrogen, linear or branched alkyl of 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl or R' and R" together form a carbonyl or spirocycloalkyl.

DETAILED DESCRIPTION OF THE INVENTION The compounds useful in the present invention provide a class of sulfamic acid esters N-acyl (or thioesters), N-acyl sulfonamides and carbamic acid esters N - Sulfonyl (or thioesters) which are inhibitors of ACAT, are now found to be useful in the treatment of cerebrovascular diseases such as seizures, peripheral vascular disease and restenosis. It has been found that the compounds of the present invention are effective in decreasing Lp (a).

In Formula I above, illustrative examples of linear or branched saturated hydrocarbon chains having from 1 to 20 carbon atoms include the methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert groups. butyl, i -pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-undecyl, n-dodecyl, n-hexadecyl, 2,2-dimethyldodecyl, 2 -tetradecyl and n-octadecyl.

Illustrative examples of hydrocarbon chains having 1 to 20 carbon atoms and having 1 to 3 double bonds include ethenyl, 2-propenyl, 2-butenyl, 3-pentyl, 2-octenyl, 5-nonenyl, 4-undecenyl , 5-heptadecenyl, 3-octadecenyl, 9-octadecenyl, 2,2-dimethyl-11-eicosenyl, 9, 12-octadecadienyl and hexadecenyl.

Linear or branched alkoxy groups having from 1 to 6 carbon atoms include, for example, methoxy, ethoxy, n-propoxy, 1-butoxy and pentyloxy.

Illustrative examples of linear or branched alkyl groups having from 1 to 6 carbon atoms as used in formula I include methyl, ethyl, n-propyl, isopropyl, n-pentyl, n-butyl and leu-butyl.

Illustrative examples of the cycloalkyl groups, as used in formula I, include cyclopentyl, cyclohexyl, cyclooctyl, tetrahydronaphthyl and 1- or 2-adamantyl.

The spirocycloalkyl groups are, for example, spirocyclopropyl, spirocyclobutyl, spirocyclopentyl and spirocyclohexyl.

Illustrative examples of the arylalkyl groups are: benzyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, benzhydryl, 2,2-diphenylethyl and 3,3-diphenylpropyl.

The pharmaceutically acceptable salts of the compounds of the formula I are also included as part of the present invention.

Base salts can be generated from compounds of Formula I by reacting the latter with an equivalent of a suitable pharmaceutically acceptable base followed by evaporation of the solvent used for the reaction and recrystallization of the ally, if required.

The compounds of Formula I can be recovered from the base salt by reacting the salt with an aqueous solution of a suitable acid such as hydrobromic, hydrochloric or acetic.

Suitable bases for forming the base salts of the compounds of this invention include amines such as triethylamine or dibutylamine or alkali metal bases and alkali metal bases. The preferred alkali metal hydroxides and alkali metal hydroxides as salt formers are the hydroxides of lithium, sodium, potassium, magnesium or calcium. Suitable classes of bases for the formation of pharmaceutically acceptable non-toxic salts are well known to practitioners of pharmaceutical formulating techniques. See, for example, Berge, SN, et al. J. Pharm. Sci. 1977; 66: 1-19.

Suitable acids for forming acid salts of the compounds of this invention contain a basic group including, but not necessarily limited to acetic, benzoic, benzensulfonic, tartaric, hydrobromic, hydrochloric, citric, fumaric, gluconic, glucuronic, glutamic, lactic, malic, maleic, methanesulfonic, pamico, salicylic, stearic, succinic, sulfuric and tartaric. Additional acid salts are formed by methods well known in the art.

The compounds of the present invention can also exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. The present invention contemplates all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic forms.

In addition, the compounds of this invention can exist in insoluble forms as well as in soluble forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, soluble forms are considered equivalent to insoluble forms for the purposes of this invention.

The preferred compounds of the present invention are those where one of the Ri and R2 are substituted phenyl and still more favored where one of the R, and R2 are phenyl substituted at positions 2, 6. In another preferred copy, R { and R2 are phenyl bisubstituted at positions 2, 6. In another preferred example, Rt is phenyl substituted at the 2, 6 position and R2 is trisubstituted at positions 2, 4, 6.

In another preferred example of the present invention, Ri is 2,6-bis (1-methylethyl) phenyl; and R 2 is 2,6-bis (1-methylethyl) phenyl or 2,4,6-tris (1-methylethyl) phenyl.

Preferred compounds of Formula I include, but are not limited to the following: Sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6-6-tris (1-methylethyl) phenyl] -acetyl] -2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2] , 4, 6-tris (1-methylethyl) phenyl] -acetyl] -2,4,6-tris (1-methylethyl) phenyl ester, Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] -acetyl] ] - 2, 4, 6 - tris (1-methylethyl) phenyl ester, Sulfamic acid [adamantaneacetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6-bis (1-methylethyl)] phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, sulfamic acid [[2,6-6-tris (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, Sulfamic acid [decanoyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [dodecanoyl] -2,6-bis (1-methylethyl) phenyl ester, 2, 6-bis (1-methylethyl) -N - [[[2,6- tris (1-methylethyl) phenyl] methyl] sulfonyl-benzeneacetamide, 2,6-bis (1-methylethyl) - N - [[ [2, 4, 6-tris (1-methylethyl) phenyl] methyl] sulfonyl] sodium salt of benzeneacetamide, 2,6-bis (1-methylethyl) phenyl [[[2, 4, 6-tris (1-methylethyl ) phenyl] methyl] sulfonyl] carbamate, 2,6-bis (1-methylethyl) phenyl [[[2,6- tris (1-methylethyl) phenyl] methyl] sulfonyl] sodium salt of carbamate, sulfamic acid ( 1-oxo-3, 3-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl (acetyl)] - 2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl (acetyl)] - 2,6- bis (1-methylethyl) phenyl ester, Sulfamic acid trans - [(2-phenylcyclopropyl) -carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2,5-dimethoxyphenyl (acetyl)] -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid [2,4,6-trimethoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2,4-6-trimethylphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-thiophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [3 - thiophenyl (acetyl)] - 2, 6 - bis (1 - methylethyl) phenyl ester, sulfamic acid [2 - methoxyphenyl (acetyl)] - 2, 6 - bis (1 - methylethyl) phenyl ester, sulfamic acid (oxofenilacetil) - 2, 6 - bis (1 - methylethyl) phenyl ester, sulfamic acid [2 - trifluoromethylphenyl (acetyl)] - 2, 6 - bis (1 - methylethyl) phenyl ester, sulfamic acid (1 - oxo - 2 - phenylpropyl) - 2, 6 - bis (1 - methylethyl) phenyl ester, sulfamic acid (ciclopentilfenilacetil) - 2, 6 - bis (1 - methylethyl) phenyl ester, sulfamic acid (cyclohexylacetyl) - 2, 6 - bis (1 - methylethyl) phenyl ester, sulfamic acid (diphenylacetyl) - 2, 6 - bis (1 - methylethyl) phenyl ester, sulfamic acid (trifenilacetil) - 2, 6 - bis (1 - methylethyl) phenyl ester, sulfamic acid [(1 - phenylcyclopentyl) carbonyl] - 2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2-phenylbutyl) -2,6-bis (1-methylethyl) ) phenyl ester, Sulfamic acid (cyclohexylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2, 2-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [(9H-fluoren-9-yl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-3-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4,6- tris (1-methylethyl) -phenyl] - 2 - propenyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4,6-tris (1-methylethyl) -phenyl] -propyl] -2,6 - bis (1-methylethyl) phenyl ester, Sulfamic acid [(acetyloxy) [2, 4, 6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methyl-ethyl) -phenyl ester, sulfamic acid [hydroxy [2, 4, 6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [fluoro [2,4,6-tris (1-methylethyl ) - phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) sodium salt of phenyl ester, Sulfamic acid [[2,4,6-tris (1-methylethyl) -phenoxy] -acetyl] -2,6-bis (1-methyl-ethyl) -phenyl ester, sulfamic acid [[2,6-bis (1 - methylethyl) - phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [[2,6-6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (phenyl) phenyl ester, The ability of the compounds of the present invention to decrease Lp (a) is summarized in Table I below. The procedure is: nine cynomogus male monkeys. { Macaca fascicularis of 4 - 5 kg) are kept in a standard food diet of monkeys (containing less than 5% fat and only trace amounts of cholesterol). The diet is available daily from 9 AM. at 2 PM. These animals carry approximately equal amounts of cholesterol in HDL (47%) and LDL (51%) and have low triglycerides compared to humans (approximately 50 mg / dL). Five weekly blood samples are taken from controlled anesthetized animals and then the animals are dosed with sulfamic acid [[2, 4, 6 - tris - (1-methylethyl) phenyl] acetyl-2,6-bis (1-methyl ethyl) phenyl ester (from here on, the compound) daily before meals (for 3 weeks at 30 mg / kg) when incorporated into oatmeal cakes (Little Debbie Snack Cakes, McKee Foods, Collegedale, Tennessee). Tang glass drinks for breakfast (Kraft General Foods, Inc. White Plains, New York) and additional cream filling is also added to the individual servings. Most of the animals consumed the drug-containing treatment immediately since they were without food during the night. They were not given their daily food until they consumed the treatment. The mean cholesterol values in the plasma (top line) and LP (a) (bottom line) are shown below (all values are in mg / dL). The treatment of the drug was in weeks 6 to 8 and are highlighted in Table I.TABLE I The average baseline values for cholesterol and Lp (a) are 154 and 16.6 mg / dL, respectively. Using these values, the percentage decreases for cholesterol and for Lp (a) by 28% and 31%, respectively. It is important to note that each animal showed a decrease in cholesterol and Lp (a), that is, there was not one that did not respond to the compound. The decrease in total cholesterol is mainly due to a decrease in LDL cholesterol.

The compounds of the present invention are then useful in pharmaceutical formulations for the treatment of seizures, peripheral vascular disease and restenosis, the compounds of Formulas I or II or the pharmaceutically acceptable salts thereof are administered to patients at levels of dosage of 250 to 3000 mg per day. For a normal adult human of approximately 70 kg of weight, this translates into a dosage of 5 to 40 mg / kg of weight per day. The specific doses employed, however, may vary depending on the requirements of the patient, the severity of the condition being treated and the activity of the compound being used. The determination of optimal doses for a particular situation is within the skills of the technique.

Claims (23)

1. CLAIMS. A method for lowering the serum or plasma level of Lp (a) in a mammal in need of such treatment, comprising administering to said mammal an amount effective to decrease the level in the plasma or serum of said Lp ( a) of a compound of the Formula: OO I I O R I or a pharmaceutically acceptable salt thereof where: X and Y are selected from oxygen, sulfur and (CR'R ") n, where n is an integer from 1 to 4 and R 'and R" are each independently hydrogen , alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, optionally substituted phenyl or R 'and R "together form a spirocycloalkyl or a carbonyl, with the proviso that at least one of the X and Y is - (CR' R" ) n - and with the additional condition when X and Y are both (CR'R "n and R 'and R" are hydrogen and n is one, Ri and R2 are aryl, R is hydrogen, a linear or branched alkyl of 1 to 8 carbon atoms or benzyl; Rj and R2 are each independently selected from: (a) phenyl or phenoxy, each of which is unsubstituted or substituted with 1 to 5 substituents selected from phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched, an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p is zero or one and each of R3 and R4 is selected from hydrogen or a linear or branched alkyl group having from 1 to 4 carbon atoms; (b) 1 - or 2-naphthyl unsubstituted or substituted with 1 to 3 substituents selected from: phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched; an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; hydroxy, phenoxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p, R3 and R4 have the meaning defined above; (c) arylalkyl; (d) a linear or branched alkyl chain having 1 to 20 carbon atoms and which is saturated or contains 1 to 3 double bonds; or (e) adamantyl or a cycloalkyl group wherein the cycloalkyl moiety has from 3 to 6 carbon atoms; with the following conditions: (i) where X is (CH2) n, Y is oxygen and Ri is a substituted phenyl, then R2 is a substituted phenyl; (ii) where Y is oxygen, X is (CH2) n, R2 is phenyl or naphthyl, then R1 is not a straight or branched alkyl chain; and (iii) the following compounds are excluded:
2. 2. A method according to Claim 1 where R? It is phenyl.
3. 3. A method according to Claim 2 wherein Ri is phenyl-substituted at positions 2, 6.
4. 4. A method according to Claim 1 wherein R2 is phenyl.
5. 5. A method according to Claim 4 wherein R2 is phenyl-substituted at positions 2, 6.
6. 6. A method according to Claim 1 where each of R { and R2 is phenyl.
7. 7. A method according to claim 6 wherein each phenyl is bisubstituted at positions 2, 6.
8. 8. A method according to Claim 1 wherein Rr is phenyl substituted at positions 2, 6 and R2 is phenyl trisubstituted at positions 2, 4, 6.
9. 9. A method according to Claim 1 wherein Rj is 2,6-bis (1-methylethyl) phenyl and R2 is 2,6-bis (1-methylethyl) phenyl or 2,4,6-tris- (1-methylethyl) phenyl
10. 10. A method according to Claim 1 wherein R j is phenyl or phenyl is substituted at positions 2, 6, where R 2 is phenyl or phenyl bisubstituted at positions 2, 6, where each of R t and R 2 is phenyl, where each phenyl is bisubstituted at position 2, 6, where Rt is phenyl substituted at positions 2, 6 and R2 is phenyl trisubstituted at positions 2, 4, 6, where Ri is 2,6-bis (1-methylethyl) phenyl and R2 is 2, 6-bis (1-methylethyl) phenyl or 2, 4, 6 -. 6 - tris (1-methyl-ethyl) phenyl, where one of Ri and R2 is the group - (CH2) t - C - (CH2) w - R7 where t is zero or 1 to 4; w is zero or 1 to 4 with the proviso that the sum of t and w is not greater than 5; R5 and R are each independently selected from hydrogen or alkyl having from 1 to 6 carbon atoms or when R5 is hydrogen, R can be selected from the groups defined by R7; and R7 is phenyl or phenyl substituted with 1 to 3 substituents selected from a linear or branched alkyl group having 1 to 6 carbon atoms, straight or branched alkoxy group having 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine , chlorine, bromine, nitro, trifluoromethyl, -COOH, COOalkyl wherein the alkyl has from 1 to 4 carbon atoms or - (CH2) pNR3R4 where P, R3 and R4 have the meaning defined above.
11. 11. A method according to Claim 1 wherein: X is oxygen, sulfur or (CR'R ") n; Y is oxygen, sulfur or (CR'R") n; with the proviso that at least one of the X or Y is (CR'R ") n where n is an integer from 1 to 4 and R 'and R" are each independently hydrogen, linear or branched alkyl of 1 to 6 carbon atoms, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R 'and R "together form a carbonyl group or a spirocycloalkyl of 3 to 10 carbons, R is hydrogen, Ri is phenyl optionally substituted, linear or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, R2 is optionally substituted phenyl, linear or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenoxy optionally replaced with the condition that only if X is (CR'R ") n R! can optionally be substituted and only if Y is (CR'R ") n R2 can optionally be substituted phenoxy and with the additional proviso that at least one of Ri and R2 are optionally substituted phenyl or phenoxy.
12. 12. A method according to Claim 1 wherein: X is oxygen; Y is (CR'R ") n where n is an integer from 1 to 2; R is hydrogen; Ri is optionally substituted phenyl; R2 is optionally substituted phenyl or phenoxy, linear or branched alkyl of 1 to 10 carbons or cycloalkyl of 3 to 10 carbons; and R 'and R "are each independently hydrogen, linear or branched alkyl of 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl or R' and R" together form a carbonyl or spirocycloalkyl.
13. 13. A method according to Claim 1 wherein the compound used is selected from: Sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6,6-tris (1-methylethyl ) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] -acetyl] -2,4,6-tris (1-methylethyl) phenyl ester, sulfamic acid [[2,6-bis] 1-methylethyl) phenyl] -acetyl] -2,4,6-tris (1-methylethyl) phenyl ester, sulfamic acid [adamantaneacetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [[2, 6-bis (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, Sulfamic acid [[2,6,6-tris (1-methylethyl) phenyl]] acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, sulfamic acid [decanoyl] -2,6-bis (1-methyl) lethyl) phenyl ester, Sulfamic acid [dodecanoyl] -2,6-bis (1-methylethyl) phenyl ester, 2,6-bis (1-methylethyl) - N - [[[2, 4, 6-tris (1 - methylethyl) phenyl] methyl] sulfonyl] benzeneacetamide, 2,6-bis (1-methylethyl) - N - [[[2,4-, 6-tris (1-methylethyl) phenyl] methyl] sulfonyl] sodium salt of benzeneacetamide, 2, 6-bis (1-methylethyl) phenyl [[[2,6- tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate, 2,6-bis (1-methylethyl) phenyl] [[[2, 4, 6-tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate sodium salt, Sulfamic acid (1-oxo-3,3-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl (acetyl)] - 2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl (acetyl)] - 2,6- bis (1-methylethyl) phenyl ester, Sulfamic acid trans - [(2-phenylcyclopropyl) -carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2,5-dimethoxyphenyl (acetyl)] -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid [2,4,6-trimethoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [2,4,6-trimethylphenyl (acetyl)] -2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-thiophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [3-thiophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-methoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (oxophenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-trifluoromethylphenyl (acetyl) ] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclopentylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclohexylacetyl) - 2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid (diphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (triphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester , Sulfamic acid [(1-phenylcyclopentyl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) ) phenyl ester, Sulfamic acid (1-oxo-2-phenylbutyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclohexylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2, 2-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [(9H-fluoren-9-yl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-3-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4,6- tris (1-methylethyl) -phenyl] - 2 - propenyl] - 2, 6 - bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4, 6-tris (1-methylethyl) -phenyl] propyl] -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid [(acetyloxy) [2, 4, 6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methyl-ethyl) -phenyl ester, sulfamic acid [hydroxy] , 4,6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [fluoro [2,4,6-tris (1-methylethyl) -phenyl]] acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester sodium salt, Acid Sulfamic [[2, 4, 6-tris (1-methylethyl) -phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6-bis (1-methylethyl) -phenoxy] ] acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [[2,6-6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (phenyl) phenyl ester,
14. 14. A method according to Claim 1 wherein the sulfamic acid [[2,4,6-tris (1-methylethyl) -phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester is administered. ? S.
15. A method for treating peripheral vascular disease which comprises "administration to a mammal in need of such treatment of a therapeutically effective amount of a compound of the Formula: O O I I R, - X - S - N - C - Y - R2 I I O R I or a pharmaceutically acceptable salt thereof where: X and Y are selected from oxygen, sulfur and (CR'R ") n, where n is an integer from 1 to 4 and R 'and R" are each independently hydrogen , alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, optionally substituted phenyl or R 'and R "together form a spirocycloalkyl or a carbonyl, with the proviso that at least one of the X and Y is - (CR' R" ) n - and with the additional condition when X and Y are both (CR'R "n and R 'and R" are hydrogen and n is one, R! and R2 are aryl; R is hydrogen, a linear or branched alkyl of 1 to 8 carbon atoms or benzyl; R1 and R2 are each independently selected from: (a) phenyl or phenoxy, each of which is unsubstituted or substituted with 1 to 5 substituents selected from; phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched, an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p is zero or one and each of R3 and R4 is selected from hydrogen or a linear or branched alkyl group having from 1 to 4 carbon atoms; (b) 1 - or 2-naphthyl unsubstituted or substituted with 1 to 3 substituents selected from: phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched; an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; hydroxy, phenoxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p, R3 and R4 have the meaning defined above; (c) arylalkyl; (d) a linear or branched alkyl chain having 1 to 20 carbon atoms and which is saturated or contains 1 to 3 double bonds; or (e) adamantyl or a cycloalkyl group wherein the cycloalkyl moiety has from 3 to 6 carbon atoms; with the following conditions: (i) where X is (CH2) n, Y is oxygen and Ri is a substituted phenyl, then R2 is a substituted phenyl; (ii) where Y is oxygen, X is (CH2) n, R2 is phenyl or naphthyl, then Rj is not a straight or branched alkyl chain; and (iii) the following compounds are excluded:
16. 16. A method according to Claim 15 wherein the compound administered is selected from: Sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6,6-tris (1-methylethyl ) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] -acetyl] -2,4,6-tris (1-methylethyl) phenyl ester, sulfamic acid [[2,6-bis] 1-methylethyl) phenyl] -acetyl] -2,4,6-tris (1-methylethyl) phenyl ester, sulfamic acid [adamantaneacetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [[2, 6-bis (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, Sulfamic acid [[2,6,6-tris (1-methylethyl) phenyl]] acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, sulfamic acid [decanoyl] -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid [dodecanoyl] -2,6-bis (1-methylethyl) phenyl ester, 2,6-bis (1-methylethyl) - N - [[[2, 4, 6-tris (1 - methylethyl) phenyl] methyl] sulfonyl] benzeneacetamide, 2,6-bis (1-methylethyl) - N - [[[2,4-, 6-tris (1-methylethyl) phenyl] methyl] sulfonyl] sodium salt of benzeneacetamide, 2, 6-bis (1-methylethyl) phenyl [[[2,6- tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate, 2,6-bis (1-methylethyl) phenyl] [[[2, 4, 6-tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate sodium salt, Sulfamic acid (1-oxo-3,3-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl (acetyl)] - 2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl (acetyl)] - 2,6- bis (1-methylethyl) phenyl ester, Sulfamic acid trans - [(2-phenylcyclopropyl) -carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2,5-dimethoxyphenyl (acetyl)] -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid [2,4,6-trimethoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [2,4,6-trimethylphenyl (acetyl)] -2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-thiophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [3-thiophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-methoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (oxophenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-trifluoromethylphenyl (acetyl) ] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclopentylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclohexylacetyl) - 2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid (diphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (triphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester , Sulfamic acid [(1-phenylcyclopentyl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) ) phenyl ester, Sulfamic acid (1-oxo-2-phenylbutyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclohexylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2, 2-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [(9H-fluoren-9-yl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-3-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4,6- tris (1-methylethyl) -phenyl] - 2 - propenyl] - 2, 6 - bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4, 6-tris (1-methylethyl) -phenyl] propyl] -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid [(acetyloxy) [2, 4, 6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methyl-ethyl) -phenyl ester, Sulfamic acid [hydroxy [2, 4, 6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [fluoro [2, 4, 6-tris ( 1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) salt sodium phenyl ester, Sulfamic acid [[2,4,6-tris (1-methylethyl) -phenoxy] acetyl] -2,6-bis (1-methyl ethyl) phenyl ester, sulfamic acid [[2,6-bis] (1-methylethyl) -phenoxy] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [[2,6-6-tris (1-methylethyl) -phenyl] -acetyl] -2,6- bis (phenyl) phenyl ester,
17. 17. A method for treating peripheral vascular disease comprising administration to a patient in need of such treatment of a compound called sulfamic acid [[2,4,6-tris (1-methylethyl) -phenyl] -acetyl] -2,6- bis (1-methylethyl) phenyl ester.
18. 18. A method for treating restenosis comprising administration to a mammal in need of said treatment of a therapeutically effective amount of a compound of the Formula: O O I I O R I or a pharmaceutically acceptable salt thereof where: X and Y are selected from oxygen, sulfur and (CR'R ") n, where n is an integer from 1 to 4 and R 'and R" are each independently hydrogen , alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, optionally substituted phenyl or R 'and R "together form a spirocycloalkyl or a carbonyl, with the proviso that at least one of the X and Y is - (CR' R" ) n - and with the additional condition when X and Y are both (CR'R "n and R 'and R" are hydrogen and n is one, Rj and R2 are aryl, R is hydrogen, a linear or branched alkyl of 1 to 8 carbon or benzyl atoms: Rj and R2 are each independently selected from: (a) phenyl or phenoxy, each of which is unsubstituted or substituted with 1 to 5 substituents selected from; phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched, an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p is zero or one and each of R3 and R4 is selected from hydrogen or a linear or branched alkyl group having from 1 to 4 carbon atoms; (b) 1 - or 2-naphthyl unsubstituted or substituted with 1 to 3 substituents selected from: phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched; an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; hydroxy, phenoxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p, R3 and R4 have the meaning defined above; (c) arylalkyl; (d) a linear or branched alkyl chain having 1 to 20 carbon atoms and which is saturated or contains 1 to 3 double bonds; or (e) adamantyl or a cycloalkyl group wherein the cycloalkyl moiety has from 3 to 6 carbon atoms; with the following conditions: (i) where X is (CH2) ", Y is oxygen and Rj is a substituted phenyl, then R2 is a substituted phenyl; (ii) where Y is oxygen, X is (CH2) n, R2 is phenyl or naphthyl, then Rj is not a straight or branched alkyl chain; and (iii) the following compounds are excluded:
19. 19. A method for treating restenosis according to Claim 18 wherein the compound administered is selected from: Sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2, 4, 6-tris] (1-Methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] -acetyl] -2,6-bis ( 1-methylethyl) phenyl ester, Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] -acetyl] -2,4,6-tris (1-methyl ethyl) phenyl ester, sulfamic acid [[2, 6-bis (1-methylethyl) phenyl] -acetyl] -2,4,6-tris (1-methylethyl) phenyl ester, sulfamic acid [adamantaneacetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [[2,6-bis (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, sulfamic acid [[2,6,6-tris (1-methylethyl]] ) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, sulfamic acid [from canoil] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [dodecanoyl] -2,6-bis (1-methylethyl) phenyl ester, 2,6-bis (1-methylethyl) -N - [[ [2, 4,6-tris (1-methylethyl) phenyl] methyl] sulfonylbenzeneacetamide, 2,6-bis (1-methylethyl) - N - [[[2,4,6- tris (1-methylethyl) phenyl] methyl] sulfonyl ] sodium salt of benzenacetamide, 2,6-bis (1-methylethyl) phenyl [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate, 2,6-bis (1-methylethyl) ) phenyl [[[2, 4, 6-tris (1-methylethyl) phenyl] methyl] sulfonyl] sodium salt of carbamate, sulfamic acid (1-oxo-3, 3-diphenylpropyl) -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl (acetyl)] - 2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl (acetyl)) - 2,6- bis (1-methylethyl) phenyl ester, Sulfamic acid trans - [(2-phenylcyclopropyl) -carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2,5-dimethoxyphenyl (acetyl)] -2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2,4,6-trimethoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, S-acid [2, 4, 6-trimethylphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [2-thiophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester , Sulfamic acid [3-thiophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-methoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Acid Sulfamic (oxophenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-trifluoromethylphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2) - phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclopentylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclohexylacetyl) -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid (diphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (triphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [(1-phenylcyclopentyl carbonyl] - 2, 6 - bis (1-methylethyl) phenyl ester, Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2-phenylbutyl) - 2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclohexylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2, 2-diphenylpropyl) -2,6- bis (1-methylethyl) phenyl ester, Sulfamic acid [(9H-fluoren-9-yl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-3-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4,6- tris (1-methylethyl) -phenyl] - 2 - propenyl] - 2, 6 - bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4, 6-tris (1-methylethyl) -phenyl] propyl] -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid [(acetyloxy) [2, 4, 6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methyl-ethyl) -phenyl ester, sulfamic acid [hydroxy] , 4,6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [fluoro [2,4,6-tris (1-methylethyl) -phenyl]] acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester sodium salt, Acid Sulfamic [[2, 4, 6-tris (1-methylethyl) -phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6-bis (1-methylethyl) -phenoxy] ] acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [[2,6-6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (phenyl) phenyl ester,
20. 20. A method for treating cerebrovascular disease comprising administration to a patient in need of such treatment of a compound called sulfamic acid [[2,4,6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis. (1-methylethyl) phenyl ester.
21. 21. A method for treating cerebrovascular disease comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound of the Formula: O O I I R, - X - S - N - C - Y - R2 O R or a pharmaceutically acceptable salt thereof where: X and Y are selected from oxygen, sulfur and (CR'R ") n, where n is an integer from 1 to 4 and R 'and R" are each independently hydrogen , alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, optionally substituted phenyl or R 'and R "together form a spirocycloalkyl or a carbonyl, with the proviso that at least one of the X and Y is - (CR' R" ) n - and with the additional condition when X and Y are both (CR'R "n and R 'and R" are hydrogen and n is one, R and R2 are aryl, R is hydrogen, a linear or branched alkyl of 1 to 8 carbon atoms or benzyl; Rj and R2 are each independently selected from: (a) phenyl or phenoxy, each of which is unsubstituted or substituted with 1 to 5 substituents selected from; phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched, an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p is zero or one and each of R3 and R4 is selected from hydrogen or a linear or branched alkyl group having from 1 to 4 carbon atoms; (b) 1 - or 2-naphthyl unsubstituted or substituted with 1 to 3 substituents selected from: phenyl, an alkyl group having 1 to 6 carbon atoms and which is linear or branched; an alkoxy group having 1 to 6 carbon atoms and which is linear or branched; hydroxy, phenoxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, - COOH, - COOalkyl where the alkyl has from 1 to 4 carbon atoms and is linear or branched, - (CH2) pNR3R4 where p, R3 and R4 have the meaning defined above; (c) arylalkyl; (d) a linear or branched alkyl chain having 1 to 20 carbon atoms and which is saturated or contains 1 to 3 double bonds; or (e) adamantyl or a cycloalkyl group wherein the cycloalkyl moiety has from 3 to 6 carbon atoms; with the following conditions: (i) where X is (CH2) n, Y is oxygen and Rj is a substituted phenyl, then R2 is a substituted phenyl; (ii) where Y is oxygen, X is (CH2) n, R2 is phenyl or naphthyl, then Rj is not a straight or branched alkyl chain; and (iii) the following compounds are excluded:
22. 22. A method for treating cerebrovascular disease according to Claim 21 wherein the compound administered is selected from: Sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2, 4, 6 - tris (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [[2,6-bis (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [[2,6- tris (1-methylethyl) phenyl] -acetyl] -2,4,6-tris (1-methylethyl) phenyl ester, sulfamic acid [[2 , 6-bis (1-methylethyl) phenyl] -acetyl] -2,4,6-tris (1-methylethyl) phenyl ester, Sulfamic acid [adamantaneacetyl] -2,6-bis (1-methylethyl) phenyl ester, Acid Sulfamic [[2,6-bis (1-methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, Sulfamic acid [[2, 4, 6-tris (1 - methylethyl) phenyl] -acetyl] -2,6-bis (1-methylethyl) phenyl ester sodium salt, Ac Sulfamic [decanoyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [dodecanoyl] -2,6-bis (1-methylethyl) phenyl ester, 2,6-bis (1-methylethyl) - N - [[[2, 4, 6-tris (1-methylethyl) phenyl] methyl] sulfonyl] benzeneacetamide, 2,6-bis (1-methylethyl) - N - [[[2, 4, 6-tris (1 - methylethyl) phenyl] methyl] sulfonyl] sodium salt of benzeneacetamide, 2,6-bis (1-methylethyl) phenyl [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate, 2, 6-bis (1-methylethyl) phenyl [[[2,4-, 6-tris (1-methylethyl) phenyl] methyl] sulfonyl] sodium salt of carbamate, sulfamic acid (1-oxo-3, 3-diphenylpropyl) - 2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (2,6-dichlorophenyl) (acetyl) ] - 2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid trans - [(2-phenylcyclopropyl) -carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2,5-dimethoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [2,4,6-trimethoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2,4,6-trimethylphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-thiophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [3-thiophenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-methoxyphenyl (acetyl)] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (oxophenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [2-trifluoromethylphenyl (acetyl) ] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclopentylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (cyclohexylacetyl) - 2, 6-bis (1-methylethyl) phenyl ester, Sulfamic acid (diphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (triphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester , Sulfamic acid [(1-phenylcyclopentyl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2-phenylbutyl) -2,6-bis (1-methylethyl) ) phenyl ester, Sulfamic acid (cyclohexylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-2, 2-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [(9H-fluoren-9-yl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid (1-oxo-3-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4, 6-tris (1-methylethyl) -phenyl] -2-propenyl] -2,6 - bis (1-methylethyl) phenyl ester, Sulfamic acid [1-oxo-3- [2, 4, 6-tris (1-methylethyl) -phenyl] propyl] -2,6-bis (1 - methylethyl) phenyl ester, Sulfamic acid [(acetyloxy) [2, 4, 6-tris (1-methylethyl) -phenyl] acetyl] -2, 6-bis (1-methyl ethyl) phenyl ester, Sulfamic acid [hydroxy [2, 4, 6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methyl-ethyl) -phenyl ester, Sulfamic acid [fluoro [2, 4, 6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis (1-methyl-ethyl) -phenyl ester, sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) - 2, 6-bis (1-methylethyl) phenyl ester sodium salt, Sulfamic acid [[2, 4, 6-tris (1-methylethyl) -phenoxy] acetyl] -2,6-bis (1-methyl-ethyl) -phenyl ester, Sulfamic acid [[2,6-bis (1-methylethyl) -phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester, sulfamic acid [[2,6,6-tris (1-methylethyl]] ) - phenyl] acetyl] -2,6-bis (phenyl) phenyl ester,
23. 23. A method for treating cerebrovascular disease comprising administration to a patient in need of such treatment of a compound called sulfamic acid [[2,4,6-tris (1-methylethyl) -phenyl] -acetyl] -2,6-bis. (1-methylethyl) phenyl ester. EXTRACT OF THE INVENTION The present invention is directed to new therapeutic uses of the compounds of the Formula (I) wherein X and Y are oxygen, sulfur or (CR'R ") n where n is 1 to 4, R is hydrogen, alkyl or benzyl, Rj and R2 are phenyl, substituted phenyl, naphthyl, substituted naphthyl, Aralkyl group, an alkyl, adamantyl or a cycloalkyl group The uses are for cerebrovascular diseases such as attacks, peripheral vascular diseases and restenosis. I I R? -X-S-N-C-Y-R2 I I O R I