MXPA99008018A - Anti-inflammatory compounds - Google Patents

Abstract

This invention relates to anti-inflammatory compounds, methods of making such compounds and methods of using such compounds having structure (I).

Description

ANTI-INFLAMMATORY COMPOUNDS BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION This invention relates to triphenylpropanamide compounds which are useful for treating inflammations but which do not demonstrate the side effects normally associated with other anti-inflammatory treatments such as glucocorticoids. This invention also relates to methods for making and using the compounds of the invention. 2. Prior Art Glucocorticoids are the only agents that reduce all the symptoms that manifest in disorders and chronic adrenocortical hyperfunctions, allergies, rheumatoid arthritis, lupus, inflammatory bowel disease, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema. Glucocorticoids also reduce the immune response in organ transplants. Undesirable side effects of these agents include hypertension, atherosclerosis, diabetes, hyperglycemia, thinning of bones and electrolyte imbalance. Mechanistically, the glucocorticoids bind to the glucocorticoid receptor (GR) on the leukocyte surface and the resulting glucocorticoid -GR complex migrates to the interior of the cell nucleus. There, the complex interacts with the transcription factor AP-1 (activation protein-1), inhibiting its induction of genes that produce inflammatory cytokines and collagenase, thus repressing the inflammatory process. However, the complex also activates GRE (glucocorticoid response element), a transcriptional activator of genes that are responsible for the undesirable side effects mentioned above. He % more desirable anti-inflammatory drug would inhibit AP-1 without activating GRE. It has been found that steroids such as dexamethasone and Prednisone exhibits potent anti-inflammatory activity, but also exhibits the side effects mentioned previously. So far, there has been no anti-inflammatory agent that does not cause side effects. In this way, new chemical agents are required that could have the desired anti-inflammatory effect without cause the side effects mentioned above. The compounds of the prior art which relate to the triphenylcyclopropyl and triphenylpropyl compounds of the invention are as < r follow: US patent. No. 3,941, 833 (Gognaco) describes certain amino derivatives of 2,2-diarylcyclopropane. They are described as useful for the treatment of cardiovascular system disorders. They are designed for systemic use. There is no indication in this patent that said compounds can or should be administered topically. There is also no indication that these compounds could be useful for treating skin inflammation. Gilbert, et al. In J. Med. Chem. 1983, 26, 693-699 report triphenylpropylidenamines and nitriles as prostaglandin synthetase inhibitors.

Blank and others in J. Med. Chem. 1969, 12, 873-876 describe the inhibition of 2,3,3-triphenylpropylamines from aldosterone biosynthesis without altering deoxycorticosterone or corticosterone levels. s. Schultz et al. In J. Med. Chem. 1967, 10, 717-724 describe diphenylpropanamides which are hypocholesterolemic in rats and inhibit the excretion of penicillin in dogs. Burch and others in Proc. Nati Acad. Sci. USA 1991, 88, 355-359 describe fluorenylpropanamides that inhibit localized inflammatory reactions in mice. German Patent No. 2,726,993 (Gognaco) describes 2,2- 15 1 -substituted diphenylcyclopropanes. The patent indicates that they are useful as vasodilators and blood pressure lowering agents. They are designed for systemic use. There is no indication in this patent that said compounds can or should be administered topically. Neither % There is no indication that said compounds could be useful for treating inflammation of the skin. Belgian Patent No. BE 855689 (Hexachemie S. A. Fr.) describes 2,2-diphenylcyclopropylmethylamides with vasodilating activity.

Precigoux et al. Describe the compound 4,4 '- (3-acetemido-2-phenylpropylidene) diphenium diacetate in Acta Crystallogr., Sect. C: Cryst. Struct. Commun., C41 (8), 1985, PP. 1244-1246. Falkenstein and others describe certain phenylaziridine compounds in "Single electron transfer versus nucleophilic ring opening in reactions of cis-trans-pairs of activated 2-phenylazidines. Strong influence of nitrogen pyramid for N-benzoylaziridines.", J. Org. Chem., 1993, 58, pp. 7377- 7381. Stamm and others describe other aziridines in "Reactions with aziridines" 53. Arene hydrides 9. Intermediate substitution in the formation of a benzylic anion by an aromatic radical anion as observed wíth 1-benzoyl-2-phenylaziridine. " Chem. Ber., 1990, 123, pp. 2227-2230. Stamm and others also described related aziridine structures in "Reductive ring opening of N-benzoylaziridine by anthracene hydride (anion of 9,10-dihydroanthracene) via base-induced fragmentation of the intermediate carbonyl adduct." J. Org. Chem., 1989, 54, pp. 1603-1607. However, none of these publications describe the structures of this invention nor do they indicate that said compounds could be useful in treating inflammation. Therefore, an object of this invention is to provide one or more compounds capable of treating inflammatory diseases.

A further object of this invention is to provide compounds capable of treating inflammatory diseases without causing side effects similar to those caused by glucocorticoids. Another object of this invention is to provide a method for manufacturing compounds for the treatment of inflammatory diseases. Another object of this invention is to provide a method for treating inflammatory diseases in mammals by administering the compounds of this invention.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to novel small molecule non-spheroidal organic compounds that exhibit the beneficial therapeutic properties of glucocorticoids, which may be free of glucocorticoid-like side effects, and which may have a high affinity for the human glucocorticoid receptor (hGR). The compounds of this invention have the following structure (I): wherein X, R1, R2, R3, R4, R5, W, Y and Z are as defined hereinafter. These compounds are useful for treating inflammatory diseases in humans and other mammals. The compounds of the present invention may also be useful in the treatment of other disorders, such as chronic adrenocorticoid disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, use as immunosuppressants in organ transplants, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema. The present invention is also directed to pharmaceutical compositions containing the compounds of the formula (I) and to methods for treating inflammation and other conditions employing said compounds. As used herein, unless otherwise indicated, alkyl and alkoxy, whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2- hexyl, 2-methylpentyl, etc. Alkoxy radicals are oxygen ethers formed from the straight or branched chain alkyl groups described above. Of course, if the alkyl or alkoxy substituent is branched there must be at least three carbon atoms in the group. The term "aryl" as used herein, alone or in combination with other terms, denotes aromatic hydrocarbon groups such as phenyl or naphthyl. The term "heteroaryl" means aromatic groups which incorporate heterogeneous atoms selected from any of S, O or N as part of the aromatic ring 1 or 2. With reference to substituents, the term "independently" means that when more than one of said substituents is possible , said substituents will be the same or different from each other.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The present invention is directed to compounds of the general formula (I): wherein X can be an individual bond or is chosen from hydrogen, sulfur or NR5, wherein R5 is selected from the group consisting of: hydrogen; I rent; cycloalkyl; alkenyl; alkyne; phenyl, wherein said phenyl group is substituted with hydrogen or one to three substituent groups, each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido , sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amino, sulfonamido or nitrile . X may also be selected from - (CH2) n, where n is an integer from 1 to 3; -HC = CH and -CHXW, where W can be oxygen, sulfur or NR5. Of course, when X is hydrogen, it does not represent a bond between the phenyl rings; wherein R1 is one to three substituent groups each selected from the group consisting of lower alkyl (C2-Cß); lower alkoxy; hydroxyl; halogen, such as chlorine, fluorine, iodine or the like; carboxyl; carboalkoxy; Not me; amido; sulfonamido or nitrile; wherein R2 is a phenyl group in which said phenyl group is substituted with hydrogen or one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; or a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or the like; wherein Y is -CH2- or hydrogen; wherein R3 is selected from the group consisting of hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen of one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; wherein Z is selected from the group consisting of carbonyl; carboxyl; carbonyl amine or sulfone; and wherein R4 is straight or branched chain alkyl having 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or the like, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from substituted or unsubstituted thiophene, furan, pyrrole, pyridine, or similar. When X is hydrogen, S or NR5, R4 can be phenyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile. Preferably, the compounds of this invention have the formula (I) above, wherein X is hydrogen and Y is hydrogen. Also preferred are the compounds of this invention in which R1 is selected from the group consisting of hydrogen and halogen. Most preferably R1 is fluorine. More preferably, the compounds of this invention have the formula (I) above, wherein X is hydrogen, Y is hydrogen, R1 is selected from the group consisting of hydrogen and halogen and R2 is selected from the group consisting of phenyl, halogen phenyl or methylenedioxy. Most preferably, R1 is fluorine or hydrogen and R2 is 4-chlorophenyl, 4-iodophenyl or 3,4-methylenedioxyphenium. Also preferred are compounds of the formula (I) wherein X is hydrogen, Y is hydrogen, R1 is selected from the group consisting of hydrogen and halogen, R2 is selected from the group consisting of phenyl, halogen phenyl or alkoxyphenyl, and R3 is selected from the group consisting of hydrogen and lower alkyl. Most preferably, R3 is hydrogen. Another preferable group of compounds of the formula (I) are those in which X is hydrogen, Y is hydrogen, R1 is selected from the group consisting of hydrogen and halogen, R2 is selected from the group consisting of phenyl and halogenofenyl, R3 is selected from the group consisting of hydrogen and lower alkyl and Z is carbonyl. Preferably, R 4 is selected from the group consisting of straight chain alkyl, phenyl lower alkyl and lower heteroaromatic alkyl. Still more preferably, R 4 is a heteroaromatic lower alkyl group. Most preferably, R 4 is 2-thiophenemethylene or 4-chlorophenylmethylene. The compounds of this invention are useful for treating inflammatory diseases such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, dermatitis and eczema. They can also be therapeutically beneficial in the treatment of other disorders including lupus, chronic adrenal disorder and hyperfunction, allergies, pneumonia, bronchial asthma, hematological disorders and Immunosuppressants in organ transplantation. They can be administered topically or systemically. It has been found that the compounds of this invention bind to hGR. However, because their structure is different from that of glucocorticoids, they appear to bind selectively to hGR, without binding to DNA and activating the GRE. This results in a potentially much lower incidence of side effects, and, consequently, longer administration periods with greater overall efficacy and relief. The compounds of this invention are optically active. The beneficial therapeutic activity may reside with any enantiomer or may be more active and advantageously used in racemic mixtures. Examples of particularly preferred compounds include: 98, 29, 33, 72, 90, 96, 84, 80, 47, 97, 123, 127, 128, 132, 140, 141, 145, 147, 150, 153, 165 , 167, 173, 174, 175, 176, 177, 178, 179 and 180. Exemplary compounds are as follows: N- (2-thiophene) acetyl-2,3,3-triphenylpropylamine N- (5-methylthiophen) acetyl -2-phenyl-3,3-bis (4-fluorophenyl) propylamine N- (3-indolyl) acetyl-2,3,3-triphenylpropylamine N-2 (carbonyl-5-methylthiophen) -2 (9H-fluor-9) -l) -2-phenylethylamine N- (2-chlorophenyl) acetyl-1, 2,2-triphenylcyclopropylmethylamine N- (2-thienyl) carbonyl-1, 2,2-trifluorylcyclopropylmethyllamine N- (phenyloxy) carbonyl-1, 2,2-triphenylcyclopropylmethylamine N- (4-chlorophenyloxy) carbonyl-1,2,2-triphenyl-cyclopropylmethylamine N- (2-pyridine) acetyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine N- (4-n-butoxyphenyl) acetyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine 5 N- (2,4-difluorophenyl) acetyl-2- (3,4-methylenedioxyphenyl) - 3,3- diphenylpropylamine N- (2-thiophene) carbonyl-2- (3,4-methylenedioxyphenyl) -3,3- diphenylpropylamine N- (3-cyanophenyl) acetyl-2- (3,4-methylenedioxyphenyl) -3,3-10 diphenylpropylamine N- (2,4-difluorophenyl) carbonyl-2- (3,4 -methylenedioxyphenyl) -3,3-diphenylpropylamine N- (4-fluorophenyl) acetyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine 15 N- (4,5-dichlorophenyl) carbonyl-2- (3, 4-methylenedioxyphenyl) -3,3-diphenylpropylamine N- (3-methylphenyl) acetyl-2- (4-trifluoromethylphenyl) -3,3-diphenylpropylamine N- (phenyl) acetyl-2- (trifluoromethylphenyl) -3 , 3-diphenylpropylamine 20 N- (5-chloro-2-benzothiophen) acetyl-2- (4-trifluoromethylphenyl) -3,3-diphenylpropylamine N- (2,4-difluorophenyl) carbonyl-2- (4-trifluoromethylphenol) -3,3-diphenylpropylamine N- (4-trifluoromethylphenyl) acetyl-2- (4-trifluoromethylphenyl) -3,3-diphenylpropylamine N- (phenyl) -acetyl-2- (4-trifluoromethylphenyl) ) -3,3-diphenylpropylamine N- (4-fluorophenyl) acetyl-2- (4-iodomethylphenyl) -3,3-diphenylpropylamine N- (3,5-bis-tri fluorophenyl) carbonyl-2- (4- yodomethyl) -3, 3- diphenylpropylamine N- (4-chlorophenyl) carbonyl-2- (4-iodomethylphenyl) -3,3-diphenylpropylamine N- (3,4-dichlorophenyl) carbonyl-2- (4-iodomethylphenyl) -3,3- diphenylpropylamine N- (2-fluorophenyl) carbonyl-2- (4-iodomethylphenyl) -3,3-diphenylpropylamine N- (2-fluorophenyl) carbonyl-2- (4-iodomethylphenyl) -3,3-diphenylpropylamine 15 N- (4 -fluorophenyl) carbonyl-2- (4-iodomethylphenyl) -3,3-diphenylpropylamine N- (4-trifluoromethylphenyl) carbonyl-2- (4-iodomethylphenyl) -3,3-diphenylpropylamine N- (3,5-bistrifluoromethylphenyl) carbonyl -2- (4-iodomethylphenyl) -3,3-20-diphenylpropylamine N- (2-thiophene) carbonyl-2- (4-iodomethylphenyl) -3,3-diphenylpropylamine N- (5-methyl-2-thiophene) carbonyl- 2- (4-iodomethyl-phenyl) -3,3-diphenyl-propylamine N- (4-chlorophenyl) carbonyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenyl-propylamine N- (2-propyl) carbonyl-1,2, 2-triphenylcyclopropylmethylamine The compounds of this invention may also include the respective hydrates of compounds specifically identified herein. The compounds of the formula I can be prepared according to the following reaction schemes. Reaction scheme 1 shows a method for manufacturing the compounds of formula I, wherein R1-R5, W, X, Y and Z are as defined above. The treatment of a diphenylmethyl-, fluorenyl- or 10,11-dihydro-5H-dibenzo (1, d) cyclohepten-4yl chloride or bromide substituted or unsubstituted with any aryl- or heteroarylacetronitrile using n-BuLi and the like or phase transfer conditions, produces nitrile intermediates of structure A. The reduction of A with LAH, NaBH4 / BH3 and the like leads to the formation of amines C. The treatment of structure A with methylene chloride in the presence of amide of potassium / liquid ammonia leads to the formation of structure B. The reduction of the nitrile group of structure B with LAH, NaBIVBHa and the like leads to an amine of structure D. Reacting C or D with acid chlorides as described below in Scheme 1 in combination with base such as NaOAc and the like, organic acids are obtained in combination with activating agents such as 1,1'-carbonyldiimidazole and the like, sulphonyl chlorides, chloroformates, isocyanates, isocyanates or a suitable organic sulfonyl chloride and compounds of structure 1. Optionally, the nitriles of structure A, when treated with diisobutylaluminum hydride (DiBAL), are converted to the aldehydes of structure E. The treatment of E with Rink resin produces resin-bound imines of structure F which are reduced with sodium triacetoxyborane to the resin-bonded mines of structure G. The treatment of G with a suitable acid in the presence of O- (7-azabenzotrans) hexafluorophosphate azol-1-yl) -N, N, N ', N'-tetramethyluron (hereinafter called "HATU") and disopropylethylamine (DIEA) produces compounds of structure I. The compounds of structure I can also be prepared by reacting amines of structure H with suitable carboxylic acids in the presence of resin-bonded 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, which is prepared from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and Merrifield resin.

SCHEME 1 NMe, N = C = NEt Merrifield Resin To prepare the pharmaceutical compositions of this invention, one or more compounds or salts thereof of the invention, As the active ingredient, it is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques, which vehicle can have a wide variety of forms depending on the desired preparation form for administration, for example, oral or parenteral. To prepare the compositions in oral dosage form, any of the normal pharmaceutical media can be used. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations, such as, for example, powders, capsules and tablets, suitable carriers and additives are used including starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets can be coated with sugar or enteric coated by standard techniques. For parenteral doses, the vehicle will normally comprise sterile water, although other ingredients may be included, for example, for purposes such as assisting in solubility or for preservation. Injectable suspensions may also be prepared, in which case suitable liquid carriers and suspending agents and the like may be employed.

The pharmaceutical compositions herein will preferably contain, per dosage unit, for example, tablet, capsule, powder, injection, spoonful and the like, from about 50 to about 100 mg. of the active ingredient, although other unit doses may be used. The compounds of this invention can also be applied or used topically. If the delivery parameters of the topically active cosmetic or pharmaceutical agent require it, the topically active composition of this invention may be further comprised of a pharmaceutical or cosmetically acceptable vehicle capable of functioning as a delivery system to enable the penetration of the topically active agent. on the skin. In alternative embodiments, the topically active pharmaceutical or cosmetic composition may optionally be combined with other ingredients such as humectants, foaming agents, cosmetic auxiliaries, antioxidants, surfactants, foaming agents, conditioners, humectants, fragrances, viscosifiers, regulating agents. of pH, preservatives and the like in an amount that does not destroy the active ingredient to produce cosmetic or pharmaceutical products. The topically active pharmaceutical or cosmetic composition should be applied in an amount effective to treat inflammation of the skin of the mammal. As used herein, "effective amount" must mean an amount sufficient to decrease inflammation of the skin of a mammal. A composition containing 0.001-10.0% active ingredient is applied to the surface of the skin when the reduction of an inflammatory condition is desired. Preferably, a composition containing 0.05-5.0% active ingredient such that on a square cm of skin surface, from about 2 μl / cm2 to about 8 μl / cm2 of agent is applied to the surface of the skin. Topically active is present when the decrease of an inflammatory condition is desired.

Table 1. Physical and biological properties of triphenylpropylamine and triphenylcyclopropylamine derivatives.

Formula page 16a hPR hGR% inh cmp R1 R R3 R4 X Y Z pf, ° C IC50 (nM) 10 μM 1 H Ph H PhCH3 H, HH, H CO 146.0-147.0 890 -0.2 2 H Ph H 2-CIPhCH2 H, HH, H CO 140.5-141.2 134 -23 3 H Ph H 4-CIPhCH2 H, HH, H CO 168.4 -170.9 480 4 4 H Ph H 4-MePhCH2 H, HH, H CO 142.3-143.6 528 12 5 H Ph H 2-MeOPhCH2 H, HH, H CO 156.9-158.9 62% 6 H Ph H 4-MeOPhCH2 H, HH , H CO 157-159 910 N) 7 H Ph H 3,4-MeOPhCH2 H, H H, H CO 123-124.5 910 11.6 8 H Ph H 2,6-diCIPhCH2 H, HH, H CO 165.2-166.5 340 3 9 H Ph H 3,4-diCIPhCH2 H, HH, H CO 65-68 1480 10 H Ph H 2-CF3PhCH2 H, HH, H CO 109-111.5 780 15 11 H Ph H 3-CF3PhCH2 H, HH, H CO 108.8-111.3 830 20 38 H Ph H 2 -thiopheneCH = CH (t) H, HH, H CO 217.3-218.9 189 39 H Ph H 3-thiopheneCH = CH H, HH, H CO 204.8-206.5 727 40 H Ph H 2 -thiophene H, HH, H SO2 169.0-170.9 151 22 41 H 4-CIPh H 2 -thiophene H, HH, H SO2 180.4-181.9 491 42 H Ph H 3-thiophene HH H, H CO 153.5-154.7 68 18 43 H Ph H 2 -benzothiophene HH H, H CO 218.3-218.8 495 44 H Ph Me 2-thiopheneCH 2 H, HH, H CO 107-109.3 133 45 H Ph H 2 -thiophene H, HH, H CO 139-142 31 5 46 H 2- thio H 2 -thiopheneCH 2 H, HH, H CO 138.2-139.9 723 47 H Ph H 3-indolCH 2 H, HH, H CO 89-93 416 17 48 H Ph H 3 -indole (CH 2) 2 H, HH, H CO 100-114 605 19 49 H Ph H 2-pyridylCH 2 H, HH, H CO 120.1-121.7 200 11 50 H Ph H NHPh H, HH, H CO 205-206 51 H Ph H 2 -MeOPhNH H, HH, H CO 203-204 32% 52 H Ph H 2-CIPhNH H, HH, H CO 210-211 273 t 53 H Ph H 2-FPhNH H, H H, H CO 190-191 293? 54 H Ph H PhCH2NH H, H HH CO 170-171 219 55 H Ph H 2,4-diCIPhCH2NH H, HH, H CO 166-167 121 56 H Ph H PhO H, HH, H CO 128-129 310 57 H Ph H 4-CIPhO H, HH, H CO 159-160 294 58 H Ph H 4-FPhO H, HH, H CO 150-151 240 59 H Ph H 2 -NapthO H, HH, H CO 151-152 155 60 H Ph H Pr H, H H, H CO 88-89 446 61 H Ph H i-Pr H, H H, H CO 114-115 584 62 H Ph H n -Bu H, HH, H CO 78-79 121 63 H Ph H ¡-Bu H, HH, H CO 112-113 316 64 H Ph H t -Bu H, HH, H CO 143-144 296 65 H Ph H CH2CO2Et H, HH, H CO 103-105.5 937 66 H Ph H PHCH2 SB H, H CO 148.7-150.8 888 18 67 H Ph H 2-MeOPhCH2 SB H, H CO 159.4-161.1 23% 68 H Ph H 2-CIPhCH2 SB HH CO 162.4-164.2 46% 69 H Ph H 2-CF3PhCH2 SB H, H CO 153.9-155 15% 70 H Ph H 2-MeOPh (CH2) 2 SB H, H CO 173.5- 175.6 53% 71 H Ph H 2-thiophene CH 2 SB H, H CO 128.7-130.5 820 16 72 H Ph H 5-Me-2-thiophene SB H, H CO 158.3-160.5 33% 73 H Ph H PhCH2 (CH2) 2 H, H CO 172.7-174.6 770 74 H Ph H 2-MeOPh (CH 2) 2 (CH 2) 2 HH CO 134.3-136.8 388 75 H Ph H 2 -thiophene CH 2 (CH 2) 2 H, H CO 175-177.5 363 76 H Ph H 3-thiophene CH 2 (CH 2) 2 H, H CO 167.3-169.3 571 77 H Ph H 5-Me-2-thiophene (CH 2) 2 H, H CO 172.1-173 882 78 H Ph H PhCH 2 H, H CH 2 CO 150-152 1200 6 79 H Ph H 3,4-MeOPhCH2 H, H CH2 CO 131-133.5 1000 24.5 80 H Ph H 2-CIPhCH 2 H, H CH 2 CO 128.5-130.5 955 -11 81 H Ph H 2 -MeOPh (CH 2) 2 H, H CH 2 CO 187.5-189 709 82 H Ph H CHPh 2 H, H CH 2 CO 166- 169 510 -20.4 83 H Ph H n-propyl H, H CH 2 CO 149-150 573 45 K 84 H Ph H -propyl H, H CH2 CO 167-168 612 15.3 85 H Ph H 2-Me-propyl H, H CH 2 CO 142-143 68% 7.2s 86 H Ph H t -butyl H, H CH 2 CO 121-122 665 12.6 87 H Ph H n -butyl H, H CH 2 CO 122-123 681 19.8 88 H Ph H 2-thiophene CH 2 H, H CH 2 CO 135-137 425 89 H Ph H 3-thiophene CH 2 H, H CH 2 CO 130-135 570 22 90 H Ph H 2 -thiophene H, H CH 2 CO 152.5-155 612 91 H Ph H 5-Me-2-thiophene H, H CH 2 CO 168-170.5 421 92 H Ph H PhNH H, H CH 2 CO 209-210 1488 -1 93 H Ph H 2 -FTHhNH H, H CH 2 CO 235-236 17% 33.9 94 H Ph H 2-MeOPhNH H, H CH2 CO 246-247 13% -18.6 95 H Ph H PhCH2NH H, H CH2 CO 231-232 4% -14.3 96 H Ph H PhO H, H CH2 CO 146-147 927 9.9 97 H Ph H 4-CIPhO H, H CH2 CO 171-172 157 12.5% molecular inhibition Comp. R1 R2 R3 R4 XYZ Mass Ion MOCH 98 H 3.4- (OCH2O) Ph H 4-CIPhCH2 H, HH, H CO 484.0 486 99 H 3.4- (OCH2O) Ph H 2 -thiopheneCH2 H, HH, H CO 455.6 456 35 100 H 3.4- (OCH2O) Ph H 3 -Me-5-CI-benzo- H, HH, H CO 554.1 554.556 18 thiophene-2-CH2 101 H 3.4- (OCH2O) Ph H 5 -CI-benzo- H, HH, H CO 540.1 540.542 26 thiophene-2-CH2 102 H 3.4- (OCH2O) Ph H 2 -pyridinoCH2 H, HH, H CO 450.5 451 51 103 H 3.4- (OCH2O ) Ph H 3-CF 3 phenyl CH 2 H, H H, H CO 517.5 518 37 104 H 3,4- (OCH 2 O) Ph H 3,5-di-CF 3 phenyl CH 2 H, H H, H CO 585.5 586 52 105 H 3.4- (OCH2O ) Ph H 4-NO 2 phenyl CH 2 H H, H CO 494.5 495 24 106 H 3.4- (OCH 2 O) Ph H 4-BuO phenyl CH 2 H, H H, H CO 521.7 522 52 ( 107 H 3.4- (OCH2O) Ph H 2 -MeOphenylCH 2 H, HH, H CO 479.6 480 28 108 H 3.4- (OCH 2 O) Ph H 3,5-di-MeOphenylCH 2 H, HH, H CO 509.6 510 38 109 H 3.4- (OCH2O) Ph H phenylCH2 H, HH, H CO 449.5 450 22 110 H 3.4- (OCH2O) Ph H 3 -FphenylCH2 H, HH, H CO 467.5 468 20 111 H 3.4- (OCH20) Ph H 2,4-diF-phen -ICH2 H, HH, H CO 485.5 486 60 112 H 3.4- (OCH2O) Ph H 2,4-d¡-CI-phenylCH2 H, HH, H CO 518.4 518.520 36 113 H 3.4- (OCH2O) Ph H 3,4-diCI-phenylCH2 H, HH, H CO 518.4 518.520 31 114 H 3.4- (OCH2O) Ph H phenylthioCH2 H, H HH CO 481.6 482 41 115 H 3.4- (OCH2O) Ph H 3-thiophene H, HH, H CO 441.5 442 28 116 H 3.4- (OCH2O) Ph H 2 -thiophene H, HH, H CO 441.5 442 62 117 H 3, 4- (OCH2O) Ph H phenyl H, HH, H CO 435.5 436 28 118 H 3.4- (OCH2O) Ph H 2 -MeO-phenyl H, HH, H CO 465.5 466 38 ( (co The following examples are merely illustrative of the compounds, methods for making such compounds, compositions and methods for using said compounds and compositions, and do not serve to limit the scope of this invention.

EXAMPLE 1 2,3,3-Triphenylpropionitrile, (Hauser, CR et al., Formation and Preferential ß-Alkylation of the Dicarbanion of 2,3,3-Tripheylpropionitrile by Menas of Potassium Amide Liquid Ammonia, J. Amer. Chem. Soc, 1959, 81, 4099-4102) as follows. A solution of phenylacetonitrile (1.00 g, 0.0086 mol) and THF (17 mL) was cooled to -78 ° C in a dry ice-acetone bath and treated by dripping with a solution of n-butyllithium in hexane (3.80 mL, 0.0095 mol). After stirring for 45 minutes at -78 ° C, a solution of diphenyl methylchloride (1.75 g, 0.0086 mol) and THF was added dropwise to give a clear yellow solution. After stirring at room temperature overnight, water (20 mL) and diethyl ether (50 mL) were added with vigorous stirring. The organic layer was separated, dried over anhydrous magnesium sulfate (MgSO), filtered and evaporated to give an oil. This material was triturated and filtered to give 1,2,2-triphenylpropionitrile.

EXAMPLE 2 9H- (Fluoren-9-yl) phenylacetonitrile was prepared using the same procedure as that described in Example 1, however, 9-bromofluorene replaced the diphenylmethyl chloride. 9H- (fluoren-9-yl) phenylacetonitrile with a melting point of 146-148.3 ° C was obtained.

EXAMPLE 3 (10,11-Dihydro-5H-dibenzo [1, d] cyclohepten-4-yl) phenylacetonitrile was made using the same procedure as described above in Example 1, with the exception that 5-chloro-10 was used, 11-dihydro-5-H-dibenzo [a, d] cycloheptene to replace diphenylmethyl chloride. (10,11-Dihydro-5H-dibenzo [1, d] cyclohepten-4-yl) phenylacetonitrile was obtained with a melting point of 134.1-147.7 ° C.

EXAMPLE 4 2- (4-Chlorophenyl) -3,3-diphenylpropionitrile was made using the same procedure as described in Example 1, but substituting phenylacetonitrile with 4-chlorophenylacetonitrile. The obtained compound had a melting point of 115.1-115.6 ° C.

EXAMPLE 5 2- (2-Thienyl) -3,3-d-phenylpropionitrile was made using the following procedure. To a mixture of 2-thiophene acetonitrile (16.30 g, 0.081 mol), benzyltriethylammonium chloride (0.185 g, 0.900081 mol) and 50% sodium hydroxide was added diphenylmethyl chloride (10.00 g, 0.081 mol) by dropping. This mixture was stirred for two hours at room temperature, heated at 40 ° C for 30 minutes and then treated with benzaldehyde (0.18 g, 0.0017 mol). The reaction mixture was poured into a water-ice mixture (200 ml) and extracted twice with dichloromethane. The organic layers were combined, washed with 2N hydrochloric acid (100 ml), water (100 ml) and saturated sodium chloride solution (100 ml), dried over magnesium sulfate, filtered and evaporated. The residue was subjected to chromatography on steaming silica to give a solid which was recrystallized three times from ethanol yielding 17.45 g (74.3%) of 2- (2-thienyl) -3,3-diphenylpropionitrile as a crystalline solid, with a spot of fusion of 102.7-105.3 ° C.

EXAMPLE 6 3,3-bis- (4-fluorophenyl) -2-phenylpropionitrile was made using the same procedure as that described in Example 5, but substituting phenylacetonitrile with 2-thiophene acetonitrile and with chlorobis (4-fluorophenyl) methane diphenylmethyl chloride. The final product had a melting point of 142.5- 143.8 ° C.

EXAMPLE 7 2- (4-Iodophenyl) -3,3-diphenylpropionitrile was made using the same procedure as that described in Example 5, but substituting 2-thiophene acetonitrile with 4-iodophenylacetonitrile.

EXAMPLE 8 1, 2,2-Triphenylcyclopropylenitrile was made using the procedure of C. R. Hauser, T. M. Harris, and T. G. Ledford [J. Amer. Chem. Soc, 1959, 81, 4099-4102]. A solution of KNH2 and liquid NH3 was prepared by adding potassium (24.5 g, 0.63 mol) to liquid NH3 (1500 ml). 2,3,3-Triphenylpropionitrile (87.5 g, 0.31 mol) was slowly added to the KNH2 / NH3 solution. After stirring for 10 minutes, this mixture was treated with a solution of dichloromethane (31.5 g, 0.37 mol) and diethyl ether (150 ml). After 1.5 hours, another portion of dichloromethane (6.0 g, 0.071 mol) and diethyl ether (25.0 ml) was added and the reaction mixture was stirred for another hour at -78 ° C. Diethyl ether was added and the NH3 was allowed to evaporate. The ether solution was washed with water, 2N hydrochloric acid and water. The organic layer was separated, dried over potassium carbonate, filtered and evaporated to a solid residue.

This material was recrystallized twice from methanol yielding 47.0 g (51%) of 1, 2,2-triphenylcyclopropylnitrile as a crystalline solid.

EXAMPLE 9 2,3,3-Triphenylpropylamine was made according to the following procedure. A solution of 2,3,3-triphenylpropionitrile (10.00 g, 0.035 mol) and THF (80 ml) was added dropwise to a solution of LiAIH4 (3.40 g, 0.089 mol) in THF (100 ml) at 0 ° C. The resulting mixture was stirred for 24 hours at room temperature and then refluxed for 24 hours. After cooling in an ice bath, the reaction mixture was treated with water (3.40 ml), 3 N sodium hydroxide (10.20 ml) and water (3.4 ml) followed by the addition of magnesium sulfate. The mixture was filtered and the filtrate was evaporated to an oil. This material was dissolved in diethyl ether (30 ml) and diethyl ether / anhydrous hydrochloric acid (25 ml, 0.025 mol) was added. A white solid was filtered and partitioned between diethyl ether and 3N sodium hydroxide. The organic layer was separated, dried over potassium carbonate, filtered and evaporated yielding 2,3,3-triphenylpropylamine as a crystalline solid.

EXAMPLE 10 2- (4-chlorophenyl) -3,3-diphenylpropylamine was made using the same procedure as described in Example 9, but substituting 2- (4-chlorophenyl) -3,3-diphenylpropionitrile for 2,3,3- triphenylpropionitrile. The final product had a melting point of 104.1-105.7 ° C.

EXAMPLE 11 2- (9H- [fIuoren-9-yl]) -2- (phenyl) ethylamine was made using the procedure described in Example 9, but substituting with 9H- (fluoren-9-yl) phenylacetonitrile at 2.3.3. -triphenylpropionitrile, and with THF diethyl ether. An oil was obtained.

EXAMPLE 12 3,3-Bis- (4-fluorophenyl) -2- (phenyl) propylamine was made using the procedure described in Example 9, but substituting 3,3-bis- (4-fluorophenyl) -2-phenylpropionitrile on 2, 3,3-Triphenylpripionitrile and with diethyl ether THF. The final product was a white solid.

EXAMPLE 13 3,3-Diphenyl-2- (2-thyl) propylamine was made using the procedure according to Example 9, but substituting 2- (2-thienyl) -3,3-diphenylpripionitrile 2.3 , 3-triphenylpropionitrile, and with THF diethyl ether. The final product was a beige colored solid having a melting point of more than 200 ° C (decomposition).

EXAMPLE 14 1,2-Triphenylcyclopropylmethylamine was made using the procedure described in Example 9, but replacing 2,3-triphenylpropionitrile with 1, 2,2-triphenylcyclopropylnitrile, and THF with diethyl ether. The final product was a white solid.

EXAMPLE 15 2- (4-Iodophenyl) 3,3-diphenylpropyl amine was made using the following procedure. A solution of TFA (3.30 g, 0.030 mol) and THF (10 ml) was added slowly to a suspension of sodium borohydride (1.10 g, 0.029 mol) and THF (20 ml) at room temperature. After concluding the gas evolution, the reaction was stirred for fifteen minutes and then treated by dripping with a solution of 2- (4-iodophenyl) -3,3-diphenylpropionitrile (4.87 g, 0.012 mol) and THF (20 ml. ). After stirring overnight at room temperature, water was slowly added followed by dichloromethane (40 ml). The organic layer was dried over potassium carbonate, filtered and evaporated to an oil. This material was dissolved in diethyl ether and treated with anhydrous hydrochloric acid / diethyl ether (10 ml). A white solid was filtered and partitioned between dichloromethane and 3N sodium hydroxide. The organic layer was separated, dried over potassium carbonate, filtered and evaporated to give 2- (4-iodophenyl) -3,3-diphenylpropylamine as a solid.

EXAMPLE 16 2- (10,1 1-Dihydro-5H-dibenzo [1, d] cyclohepten-4-yl) -2- (phenyl) ethylamine was made as follows. A solution of BH3 1M-THF (24 ml, 0.024 mol) at room temperature was treated with a solution of 10.1 1-dihydro-5H-dibenzo [1, d] cyclohepten-4-yl) phenylacetonitrile (5.0 g, 0.016 mol) and THF (70 ml). The resulting solution was refluxed for 2 hours, cooled to 0 ° C and treated with methanol (50 ml) followed by 6N hydrochloric acid (125 ml). The mixture was heated at 70 ° C for 1 hour, cooled to 50 ° C, adjusted to pH 12 with a 50% sodium hydroxide solution and extracted twice with ethyl acetate. The organic layers were combined, dried, filtered and evaporated to a yellow oil. This material was triturated with hexane and filtered. The filtrate was evaporated and the residue was subjected to silica gel chromatography using ethyl acetate: hexane (8: 2) as the eluent to give a yield of 2.29 g (46%) of 2- (10.1 1- dihydro-5H-dibenzo [1, d] cyclohepten-4-yl) -2- (phenyl) ethylamine as an oil.

EXAMPLE 17 The compound 29 was made in accordance with the following procedure. A solution of thiopheneacetyl chloride (0.281 g, 0.0017 mol) and ethylene dichloride (8.0 ml) was added slowly to an ice-cooled mixture of 2,3,3-triphenylpropylamine (0.50 g, 0.0017 mol), sodium acetate ( 0.18 g, 0.0022 mol) and ethylene chloride (8.0 ml). After stirring overnight at room temperature, water was added with careful mixing. The resulting organic layer was separated, washed successively with 1 N sodium hydroxide solution and 1 N hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated to an oil which solidified. Two recrystallizations of this material produced 0.410 g (59%) of 29 as a crystalline solid, which had a melting point of 130-132 ° C.

EXAMPLE 18 Other compounds can be obtained according to the procedure mentioned in example 17, requiring the substitution of thiopheneacetyl chloride or 2,3,3-triphenylpropylamine, such as the compounds: 1, 6, 7, 18, 29, 78, 79 , and 82.

EXAMPLE 19 Compound 80 was made using the following procedure: a solution of 2-chlorphenylacetic acid (0.289 g, 0.0017 mol), 1, V-carbonyldiimidazole (0.271 g, 0.0017 mol) and acetonitrile (25 ml) was stirred for twenty minutes at room temperature environment and treated with 1,2,2-triphenylcyclopropylmethylamine (0.500 g, 0.0017 mol). After stirring for 24 hours, the reaction was evaporated and the residue was dissolved in methylene dichloride. This solution was washed with water (10 ml), 1 N HCl (10 ml) and water (10 ml). The organic layer was separated, dried over magnesium sulfate, filtered and evaporated to an oil. This material was dissolved in ethylene dichloride and diethyl ether was added causing a crystalline solid to form. Filtration gave 0.501 g (65%) of 80 as a crystalline solid with a melting point of 128.5-130.5 ° C.

EXAMPLE 20 After the procedure of example 19, substituting the acid 2-chlorophenylacetic acid or 1,2,2-triphenylcyanopropylmethylamine by equivalent amounts of the appropriate starting materials and replacing the acetonitrile used therewith with ethylene dichloride, the following compounds can be obtained: 2, 3, 4, 5, 8, 9, 10 , 11, 12, 13, 14, 19, 20, 21, 22, 24, 25, 26, 27, 28, 30, 34, 37, 38, 39, 40, 41, 42, 43, 45, 46, 48 49, 61, 62, 63, 64, 81, 83, 84, 85, 86, 87, 88, 89 and 90.

EXAMPLE 21 Compound 66 was made as follows: a solution of phenylacetic acid (0.30 g, 0.0024 mol), 2- (9H- [fluoren-9-yl]) - 2- (phenyl) ethylamine (0.70 g, 0.0024 mol) and ethylene dichloride (10 ml) was treated with 1- (3- hydrochloride. dimethylaminopropyl) -3-ethylcarbodiimide (0.55 g, 0.0029 mol). After stirring overnight, the reaction solution was washed with 3N sodium hydroxide, 6N HCl and saturated NaCl solution. The organic layer was separated, dried over magnesium sulfate and evaporated to a semi-solid. This material was triturated with diethyl ether and filtered to give a solid which was recrystallized from methanol yielding 0.12 g (12%) of compound 66 as a white crystalline solid having a melting point of 148.7-150.8 ° C.

EXAMPLE 22 Following the procedure of Example 21, substituting phenylacetic acid or 2- (9H- [fluoren-9-yl]) - 2- (phenyl) ethylamine for equivalent amounts of the appropriate starting materials, the following compounds can be obtained: , 16, 17, 23, 31, 32, 44, 65, 67, 68, 69, 70, 71, 72, 74, 75, 76, 77, and 91.

EXAMPLE 23 Compound 52 was made according to the following procedure: a solution of 2,3,3-triphenylpropylamine (0.25 g, 0.0009 mol) and methylene dichloride (25 ml) was treated with 2-chlorophenyl isocyanate (0.13 g, 0.0009 mol) at room temperature. A solid formed which was filtered and recrystallized from methanol-hexane to give 0.14 g (75%) of 52 as a white crystalline solid having a melting point of 210-21 1 ° C.

EXAMPLE 24 Following the procedure of Example 23, substituting the chlorophenyl isocyanate or the 2,3,3-triphenylpropylamine used there for equivalent amounts of the suitable starting materials, the following compounds can be obtained: 50, 51, 53, 54, 55, 92 , 93, 94, and 95.

EXAMPLE 25 Compound 40 was made as follows: an ice-cooled solution of 2,3,3-triphenylpropylamine (0.674 g, 0.0024 mol) and CHCl3 (20 ml) was treated with 2-thiophenesulfonyl chloride (0.475 g, 0.0026 mol) followed by diisopropylethylamine (0.764 g, 0.0059 mol) and stirred at room temperature overnight. The reaction was washed with 1 N HCl (20 mL) and saturated NaCl solution. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated yielding 0.660 g (66%) of 40 as a solid having a melting point of 169-170.9 ° C.

EXAMPLE 26 Following the procedure of Example 25, substituting the 2,3,3-triphenylpropylamine used therein with an equivalent amount of 2- (4-chlorophenyl) -3,3-diphenylpropylamine, compound 41 can be obtained.

EXAMPLE 27 Compound 57 was made according to the following procedure: to a solution of 2,3,3-triphenylpropylamine (0.25 g, 00009 mol), triethylamine (0.09 g, 0.0009 mol) and CHCl3 (25 ml) was added chloroformate of 4-fluorophenyl (0.2 g, 0.0009 mol) and the resulting solution was stirred for 45 minutes. The reaction was then washed with 1 N HCl and brine. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated to a white solid. This material was recrystallized from methanol / hexane to give 0.15 g (39%) of 57 as a white crystalline solid having a melting point of 150-151 ° C.

EXAMPLE 28 Following the procedure of example 27, but substituting the 2,3,3-triphenylpropylamine and the 4-phorophenyl chloroformate used therein with equivalent amounts of suitable starting materials, the following compounds can be obtained: 56, 58, 59, 96 and 97.

EXAMPLE 29 Compound 17 was made as follows: a mixture of N- [3,3-bis- (4-fluorophenyl) -2-phenylpropyl] -2-phenylacetamide [compound 18] (0.84 g, 0.0019 mol), dimethyl sulfate ( 0.37 g, 0.0029 mol), benzyltriethylammonium chloride (0.14 g, 0.00075 mol) and 50% NaOH (30 ml) was stirred overnight at room temperature. Water was added and the mixture was extracted with an ethylene dichloride. The organic layer was separated, dried over potassium carbonate, filtered and evaporated to an oil which was recrystallized from diethyl ether-hexane giving 0.080 g (9%) of 17 as a yellow crystalline solid having a fusion of 86.9-88.2 ° C.

EXAMPLE 30 Compound 98 was prepared as follows: a mixture of 2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine (18.0 g, 0.055 mol) and anhydrous THF (120 mL) at -70 ° C was treated by dripping with a 1.0 M solution of DiBAL (100 mL, 0.1 10 mol). The reaction was stirred for one hour at -70 ° C and then at ° C for 1.5 hours. The reaction was cooled to 0 ° C and treated with ethanol (20 mL) followed by 10% aqueous HCl (150 mL). Extraction with ethyl acetate, drying over anhydrous MgSO 4, evaporation and purification by flash chromatography (silica gel) yielded 2- (3, 4-methylenedioxyphenyl) -3,3-diphenylpropionic acid as a solid. A mixture of this material (8.0 g, 0.024 mol), Rink's amine resin (8.73 g, 0.0044 mol) and trimethylortoformate (60 mL) was stirred for 4 days, filtered and washed twice with trimethylorthoformate, methylene chloride and dichloroethane. The resulting resin was stirred with NaBH (Oac) 3 (4.63 g, 0.022 mol), acetic acid (1.83 mL) and dichloroethane (60 mL) for two days. The resulting resin was washed with methanol, methylene chloride, 10% acetic acid / methylene chloride, 10% triethylamine / methylene chloride, methylene chloride and methanol. This resin (0.235 g, 0.0001 mol) was stirred for two days with HATU (0.090 g, 0.00024 mol), diisopropylethylamine (175 μL), 4-chlorophenylacetic acid (0.085 g, 0.0005 mol) and DMF (2 mL). The resin was filtered and washed three times each with DMF, methylene chloride and methanol, and dried. The dried resin was treated with 10% TFA / methylene chloride and filtered. The filtrate was blown to dry with nitrogen to give 0.042 g (87%) of compound 98, mass spectrometry by electrospray e / m = 484.

EXAMPLE 31 Following the procedure of Example 30, but substituting the 4-chlorophenylacetic acid and the 2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine used therein with equivalent amounts of suitable starting materials, the following compounds can be obtained. -161, 164, 168, 173, 174, 176-178, 180, and 182.

EXAMPLE 32 Compound 162 was prepared as follows: a solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (7.67 g, 0.040 mol) and methylene chloride (300 mL) was washed with 10% NH OH, dried on MgSO, filtered and evaporated. The residue was dissolved in DMF (100 mL) and mixed with Merrifield resin (20.0 g, 0.020 mol) at 100 ° C overnight. The mixture was filtered and the resin was washed with DMF, methanol and methylene chloride. A mixture of this resin (0.48 g, 0.00048 mol), 4-chlorophenylacetic acid (0.0205 g, 0.00012 mol), 2 (4-iodophenyl) -3,3-diphenylpropylamine (0.0413 g, 0.0001 mol) and CHCI3 (2.0 mL) it was stirred for two days, filtered and washed with CHCl3. The filtrate was blown dry with nitrogen to yield compound 163, 0.0425 g, (88%), chlorine mass spectrometry e / m = 483.99.

EXAMPLE 33 Following the procedure of Example 32, but substituting the 4-chlorophenylacetic acid used therein with equivalent amounts of the suitable starting materials, the following compounds can be obtained: 163, 165-167, 169-172, 175, 179, 181 and 183 .

EXAMPLE 34 A human glucocorticoid receptor binding test was carried out to determine the degree to which the compounds of this invention have the ability to bind to human glucocorticoid receptors. This binding capacity can be indicative of the anti-inflammatory activity of the compound. The test was carried out as follows. Human glucocorticoid receptors of insect cells (Sf21) infected with baculovirus hGR or a lymphoblast cell line expressing high levels of endogenous hGR (IM9) were prepared. The receptor binding reactions, with or without test compounds, were established in 96-well microtiter plates that were previously silica gel-coated with SIGMACOTE ™, a chlorinated organopolysiloxane in heptane. The binding components, acetonide of 3 (H) triamcinolone (TAA), pH regulator containing glycerol / molybdate and unlabeled compounds were added to the wells using a combination of a BIOMEK laboratory automation system and repeating pipettes.

After four hours of incubation, the samples were precipitated with polyethylene glycol and filtered through Whatman CF / F paper using a TOMTEK cell cultivator. The filter coupled with 96 samples was attached to a solid phase scintillator and counted directly in a counter BETAPLATE. The IC50 values were determined based on the competence of 3H TAA with the test compounds at concentrations of 6-8 ranging from 10 ~ 10 -10"5 M and were calculated using the Chung-Prusoff equation The activity of the test compounds to displace 3 (H) TAA bound to hGR is also expressed as a percentage inhibition to 1 μM The results of this test are shown later in Table 1.

EXAMPLE 35 A test for binding to the human progesterone receptor was performed in order to determine the selectivity of the compounds, as indicated below. Human progesterone receptors were prepared from insect cells (SF21) infected with hPR A baculovirus, or from a breast cancer cell line, T47D, which expresses high levels of endogenous hPR. The receptor binding reactions, with or without test compounds, were prepared in 96 well cavity microtiter plates that were previously siliconized with SIGMACOTE. The binding components, 3 (H) R5020 Promegestone, a high affinity ligand for progesterone receptors, glycerol / molybdate containing regulator and unlabeled compounds were added to the wells using a combination of BIOMEK laboratory automation system and pipettes of repetition.

After overnight incubation, the samples were precipitated with polyethylene glycol and filtered through Whatman GF / F paper using a TOMTEK cell cultivator. The filter coupled with 96 samples were joined to a solid phase scintillator and directly counted in the counter BETAPLATE. Only those compounds that were active in the human glucocorticoid receptor test presented in Example 30 were used for binding to the progesterone receptor to determine cross-reactivity profiles, if any. The activity of test compounds to displace 3 (H) R5020 bound to hPR is expressed as a percent inhibition at the two concentrations, 10"6 and 10 ~ 5 Molar, those compounds that do not inhibit 3 (H) TAA bound by 50 % to 10"5 M were not considered active. Surprisingly, the compounds of this invention bind selectively to hGR but show little or no affinity for hPR.

EXAMPLE 36 Various triphenylpropanamide compounds of this invention, which have various affinities for the human glucocorticoid receptor, were tested for topical anti- inflammatory activity in mouse ear inflammation models. Compounds with low affinity to the receptor (IC50> 20 nM) were very inactive or inactive to reduce ear inflammation induced by contact with the oxazolone sensitizer. Compounds that have receptor affinities close to hydrocortisone were almost as active as hydrocortisone in suppressing mouse-induced oxazolone-induced hypersensitization (MOCH) and edema of the ear induced by phorbol ester. The in vivo studies of this example were carried out as indicated below. 7-8 week old male albino CD-1 mice were used in this example. A solution of arachidonic acid (AA) 0.005% (w / v) TPA or 20% (w / v) was made in acetone. A volume of 20 μl of TPA or AA was applied to the left dorsal ear of the mouse. The compounds of this invention were placed in a composition containing ethanol / propylene glycol in a ratio of 70:30, were applied to the left ear of each mouse in an amount of 20 μl immediately after the application of TPA or AA. The right ear did not receive treatment. Mice were sacrificed by inhalation of carbon dioxide 5.5 hours after the administration of TPA and one hour after administration of AA, the left and right ears were removed and a 7 mm biopsy was removed from each ear and weighed. The difference in weight of the biopsy between the right and left ear was calculated. The anti-inflammatory effects of the compounds were evident as an inhibition of the increase in the weight of the ear.

To determine MOCH using the compounds of this invention, male 7-8 week old albino CD-1 mice were induced in the shaved abdomen with 50 μl of 3% oxazolone in acetone / corn oil (day 0). ). On the 5th day, 20 μl of 2% volume of oxazolone in acetone was applied to the dorsal left ear of the mouse. The compounds (made in ethanol / propylene glycol 70:30) were applied to the left ear in a volume of 20 μl, one hour after the oxazolone attack. The right ear did not receive treatment. Mice were sacrificed by inhalation of carbon dioxide 24 hours after the oxazolone attack, the left and right ears were removed and a 7mm boppy was removed from each ear and then weighed. The difference in weight of the biopsy between the right and left ear was calculated. The anti-inflammatory effects of the compounds were evident as an inhibition of the increase in the weight of the ear. The results of the following in vivo test are shown in table 2: TABLE 2 Ear swelling by Oxazolone (MOCH) Item No.% inhibition vs. 1 mg vehicle. 2 4 4 1 5 13 6 38 9 18 10 19 11 33 12 36 13 10 14 11 15 47 16 46 19 2 20 32 22 15 10 23 41 24 21 25 9 26 -5 27 20 28 28 29 83 30 21 31 14 32 83 33 74 34 29 15 35 36 36 13 37 25 38 13 39 24 40 15 41 3 42 27 43 47 44 3 45 31 46 4 48 22 49 20 50 30 53 24 54 10 55 18 56 38 57 13 58 16 60 27 61 17 62 36 63 3 64 26 65 13 66 20 68 28 69 43 72 50 74 18 75 26 76 23 77 41 79 18 80 54 81 22 82 23 83 -4 84 54 84 16 87 22 88 29 89 16 90 65 91 13 92 42 93 26 94 35 95 16 96 52 97 50 98 85 hydrocortisone 75-85 According to the previous table, for example, the compounds 23, 15, and 16 had moderate topical activity while the compounds 29, 32, and 98 were equiactive with hydrocortisone. Compounds 29 and 32 were tested for dose related activity in the oxazolone model. As shown in Table 3, both compounds inhibited swelling of the ear in a dose-dependent manner.

TABLE 3 Swelling of the ear by Oxazolone% Inhibition vs. Vehicle Treatment Experiment 1 Experiment 2 Dose (%) Hydrocortisone 78.9 58.2 1 Compound 29 66.5 49.9 1 34.7 0.3 4.3 0.1 Compound 32 36.5 31.45 1 18.95 0.3 11.2 0.1 Both compounds were tested in a model of ear edema induced with TPA, which also shows glucocorticoid effect. In equivalent doses, the two non-steroidal compounds were slightly less active than hydrocortisone, as shown in the following table 4.

TABLE 4 Edema of the ear by% Treatment Dose% Inhibition of TPA Hydrocortisone 1 80.6 Compound 29 1 64.9 Compound 32 1 60.0 These tests demonstrate that the compounds of the invention (triphenylpropanamides) are topically active as anti-inflammatory agents. Due to their selective effects on transcription factors, they should not cause the side effects associated with classical glucocorticoids. In addition to inflammation, the triphenylpropanamides of this invention may be useful as therapeutics in other skin conditions in response to glucocorticoids.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound that has the formula: wherein X can be an individual bond, hydrogen, sulfur or NR5, (CH2) n wherein n is an integer from 1 to 3; -HC = CH; and -CHXW, wherein W can be oxygen, sulfur or NR5; R1 is one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl; halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; R2 is a phenyl group in which said phenyl group is substituted with hydrogen or one to three substituent groups each selected from the group consisting of lower alkyl (C2-Ce), lower alkoxy, hydroxyl, halogen, carboxy, carboalkoxy, amino , amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; And it is -CH2- or hydrogen; R3 is selected from the group consisting of hydrogen; I rent; cycloalkyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; Z is selected from the group consisting of carbonyl; carboxyl; carbonylamino or sulfone; R4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted or unsubstituted thiophene, furan, pyrrole, or pyridine, and R5 it is selected from the group consisting: hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or one to three substituent groups, each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido , sulfonamide or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, alkoxy Bottom, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amino, sulfonamido or nitrile; 2. A compound according to claim 1, further characterized in that R1 is selected from the group consisting of hydrogen and halogen group. 3. A compound according to claim 2, further characterized in that R1 is hydrogen. 4. A compound according to claim 2, further characterized in that R1 is halogen. 5. A compound according to claim 4, further characterized in that R1 is fluorine. 6. A compound according to claim 1, further characterized in that X is hydrogen. 7. A compound according to claim 1, further characterized in that Y is hydrogen. 8. A compound according to claim 1, further characterized in that R2 is selected from the group consisting of phenyl and halogenphenyl. 9. A compound according to claim 8, further characterized in that R2 is phenyl. 10. - A compound according to claim 8, further characterized in that R2 is halogenphenyl. 1 1. A compound according to claim 10, further characterized in that R2 is chlorophenyl. 12. A compound according to claim 1, further characterized in that R3 is selected from the group consisting of hydrogen and lower alkyl. 13. A compound according to claim 12, further characterized in that R3 is hydrogen. 14. A compound according to claim 1, further characterized in that R4 is selected from the group consisting of straight chain alkyl, phenylalkyl lower and heteroaromatic lower alkyl. 15. A compound according to claim 14, further characterized in that R4 is heteroaromatic lower alkyl. 16. A compound according to claim 15, further characterized in that R4 is thiophene. 17. A compound according to claim 1, further characterized in that Z is carbonyl. 18.- A compound that has the formula: where X is hydrogen; R1 is selected from the group consisting of hydrogen and halogen group; R2 is a phenyl group in which said phenyl group is substituted with hydrogen or one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxy, carboalkoxy, amino , amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; And it's hydrogen; R3 is selected from the group consisting of hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; Z is selected from the group consisting of carbonyl; carboxyl; carbonylamino or sulfone; and R 4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from substituted or unsubstituted thiophene, furan, pyrrole, or pyridine. 19. A compound according to claim 18, further characterized in that R1 is hydrogen. 20. A compound according to claim 18, further characterized in that R1 is halogen. 21. A compound according to claim 20, further characterized in that R1 is fluorine. 22. A compound according to claim 18, further characterized in that R2 is selected from the group consisting of phenyl, halogenphenyl and thio. 23. A compound according to claim 22, further characterized in that R2 is phenyl. 24. A compound according to claim 23, further characterized in that R2 is halogenphenyl. 25. - A compound according to claim 24, further characterized in that R2 is chlorophenyl. 26. A compound according to claim 18, further characterized in that R3 is selected from the group consisting of hydrogen and lower alkyl. 27. A compound according to claim 26, further characterized in that R3 is hydrogen. 28. A compound according to claim 18, further characterized in that R4 is selected from the group consisting of straight chain alkyl, phenylalkyl lower and heteroaromatic lower alkyl. 29. A compound according to claim 28, further characterized in that R4 is heteroaromatic lower alkyl. 30. A compound according to claim 29, further characterized in that R4 is thiophene. 31.- A compound that has the formula: (OR where X is hydrogen; And it's hydrogen; R1 is selected from hydrogen and halogen; R2 is selected from phenyl and halogenphenyl; R3 is selected from the group consisting of hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; Z is selected from the group consisting of carbonyl; carboxyl; carbonylamino or sulfone; and R 4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from substituted or unsubstituted thiophene, furan, pyrrole or pyridine. 32. A compound according to claim 31, further characterized in that R3 is selected from the group consisting of hydrogen and lower alkyl. 33. - A compound according to claim 32, further characterized in that R3 is hydrogen. 34. A compound according to claim 31, further characterized in that R4 is selected from the group consisting of straight chain alkyl, lower phenylalkyl, and heteroaromatic lower alkyl. 35. A compound according to claim 34, further characterized in that R4 is heteroaromatic lower alkyl. 36. A compound according to claim 35, further characterized in that R4 is thiophene. 37. A compound according to claim 31, further characterized in that Z is carbonyl. 38.- A compound that has the formula: where X is hydrogen; And it's hydrogen; R1 is selected from hydrogen and halogen; R2 is selected from phenyl and halogenphenyl; R3 is selected from hydrogen and lower alkyl; Z is selected from the group consisting of carbonyl; carboxyl; carbonylamino or sulfone; and R 4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted or unsubstituted thiophene, furan, pyrrole or pyridine. 39.- A compound according to claim 38, further characterized in that R3 is hydrogen. 40.- A compound according to claim 38, further characterized in that R3 is methyl. 41. A compound according to claim 38, further characterized in that R4 is selected from the group consisting of straight chain alkyl, phenylalkyl lower and heteroaromatic lower alkyl. 42. A compound according to claim 41, further characterized in that R4 is heteroaromatic lower alkyl. 43. A compound according to claim 42, further characterized in that R4 is thiophene. 44. A compound according to claim 38, further characterized in that Z is carbonyl. 45.- A compound that has the formula: where X is hydrogen; And it's hydrogen; R1 is selected from hydrogen and halogen; R2 is selected from phenyl and halogenphenyl; R3 is selected from hydrogen and lower alkyl; Z is carbonyl; and R 4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from substituted or unsubstituted thiophene, furan, pyrrole or pyridine. 46. A compound according to claim 45, further characterized in that R4 is selected from the group consisting of straight chain alkyl, lower phenylalkyl and lower heteroaromatic alkyl. 47. A compound according to claim 46, further characterized in that R4 is lower alkyl heteroaromatic. e5 48. A compound according to claim 47, further characterized in that R4 is thiophene. 49. An anti-inflammatory composition comprising a pharmaceutically acceptable carrier and an anti-inflammatory effective amount of a compound having the formula: wherein X is an individual bond, hydrogen, sulfur or NR5, (CH2) n wherein n is an integer from 1 to 3; -HC = CH; and -CHXW, wherein W can be oxygen, sulfur or NR5. R1 is one to three substituent groups each selected from the group consisting of lower alkyl (C2-Ce), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; R2 is a phenyl group in which said phenyl group is substituted with hydrogen or one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxy, carboalkoxy , amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; And it is -CH2- or hydrogen; R3 is selected from the group consisting of hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, alkoxy Bottom, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; Z is selected from the group consisting of carbonyl; carboxyl; carbonylamino or sulfone; R4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted or unsubstituted thiophene, furan, pyrrole, or pyridine, and R5 it is selected from the group consisting: hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or one to three substituent groups, each selected from the group consisting of lower alkyl (C2-Ce), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amino, sulfonamido or nitrile; 50.- A composition according to claim 49, further characterized in that R1 is selected from the group consisting of hydrogen and halogen group. 51. A compound according to claim 50, further characterized in that R1 is hydrogen. 52. A compound according to claim 50, further characterized in that R1 is halogen. 53. A compound according to claim 52, further characterized in that R1 is fluorine. 54.- A compound according to claim 49, further characterized in that X is hydrogen. 55.- A compound according to claim 49, further characterized in that Y is hydrogen. 56. A compound according to claim 49, further characterized in that R2 is selected from the group consisting of phenyl and halogenphenyl. 57. A compound according to claim 56, further characterized in that R2 is phenyl. 58.- A compound according to claim 57, further characterized in that R2 is halogenphenyl. 59. - A compound according to claim 58, further characterized in that R2 is chlorophenyl. 60. A compound according to claim 49, further characterized in that R3 is selected from the group consisting of hydrogen and lower alkyl. 61.- A compound according to claim 60, further characterized in that R3 is hydrogen. 62. A compound according to claim 49, further characterized in that R4 is selected from the group consisting of straight chain alkyl, phenylalkyl lower and heteroaromatic lower alkyl. 63. A compound according to claim 62, further characterized in that R4 is heteroaromatic lower alkyl. 64.- A compound according to claim 63, further characterized in that R4 is thiophene. 65.- A compound according to claim 49, further characterized in that Z is carbonyl. 66.- A method to make a compound that has the formula: (0 wherein X is an individual bond, hydrogen, sulfur or NR5, (CH2) n wherein n is an integer from 1 to 3; -HC = CH; and -CHXW, wherein W can be oxygen, sulfur or NR5; R1 is one to three substituent groups each selected from the group consisting of lower alkyl (C2-Ce), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; R2 is a phenyl group in which said phenyl group is substituted with hydrogen or one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxy, carboalkoxy, amino , amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; And it is -CH2- or hydrogen; R3 is selected from the group consisting of hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; Z is selected from the group consisting of carbonyl; carboxyl; carbonylamino or sulfone; R4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; and R5 is selected from the group consisting: hydrogen; I rent; cycloalkyl; alkenyl; alkyne; phenyl, wherein said phenyl group is substituted with hydrogen or one to three substituent groups, each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen, carboxyl, carboalkoxy, amino, amino, sulfonamido or nitrile comprising the steps of (1) reacting R2CH2CN with a compound having the formula (II) in the presence of nBuLI: W = CI, Br to obtain a compound having the formula (III) (2) reacting said compound of formula (III) with LAH to form a compound of formula (IV): and (3) reacting said compound of the formula (IV) with compound selected from the group consisting of: (a) sodium acetate and R4COCI; (b) CDI and R4CO2H; (c) EtN = C = N (CH2) 3NMe2 HCl; (d) R 4 CO 2 H; (e) CICO2R4; (f) CIC = O (NHR4); and (g) R4SO2CI to obtain a compound of the formula (I). 67.- A method for making a compound having the formula: wherein X is an individual bond, hydrogen, sulfur or NR5, (CH2) n where n is an integer from 1 to 3; -HC = CH; and -CHXW, wherein W can be oxygen, sulfur or NR5; R1 is one to three substituent groups each selected from the group consisting of lower alkyl (C2-Ce), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; R2 is a phenyl group in which said phenyl group is substituted with hydrogen or one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxy, carboalkoxy, amine, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; R3 is selected from the group consisting of hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; Z is selected from the group consisting of carbonyl; carboxyl; carbonylamino or sulfone; R4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; and R5 is selected from the group consisting: hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or one to three substituent groups, each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido , sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amino, sulfonamido or nitrile comprising the steps of (1) reacting R2CH2CN with a compound having the formula (II) in the presence of nBuLI: (II) W = CI, Br to obtain a compound having the formula (III) (2) reacting said compound of the formula (III) with CH2Cl2 in the presence of KNH2 and liquid NH3 to obtain a compound having the formula (V): (3) reacting said compound of the formula (V) with LAH to form a compound of the formula (VI): and (4) reacting said compound of the formula (VI) with a compound selected from the group consisting of: (a) sodium acetate and R4COCI; (b) CDI and R4CO2H; (c) EtN = C = N (CH2) 3NMe2 HCl; (d) R 4 CO 2 H; (e) CICO2R4; (f) CIC = O (NHR4); and (g) R4SO2CI to obtain a compound of the formula (I). 68.- A method to make a compound that has the formula: wherein X is an individual bond, hydrogen, sulfur or NR5, (CH2) n wherein n is an integer from 1 to 3; -HC = CH; and -CHXW, wherein W can be oxygen, sulfur or NR5; R1 is one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; R2 is a phenyl group in which said phenyl group is substituted with hydrogen or one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxy, carboalkoxy , amine, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; And it is -CH2- or hydrogen; R3 is hydrogen; Z is selected from the group consisting of carbonyl; carboxyl; carbonylamino or sulfone; R4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as thiophene, furan, pyrrole, substituted or unsubstituted pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; and R5 is selected from the group consisting: hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or one to three substituent groups, each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido , sulfonamide or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amino, sulfonamido or nitrile comprising the steps of (1) reacting DiBAL with a compound having the formula (VII): (VII) to obtain a compound having the formula (VIII) (2) reacting said compound of the formula (VIII) with Rink resin to obtain a resin binding compound of the formula (IX): (3) reacting said compound of the formula (IX) with sodium triacetoxyborohydride to form a compound of the formula (X): (4) reacting said compound of the formula (X) with R 4 CO 2 H in the presence of HATU and DIEA followed by treatment with TFA to form a compound of the formula (I). 69.- A method to make a compound that has the formula: wherein X is an individual bond, hydrogen, sulfur or NR5, (CH2) n wherein n is an integer from 1 to 3; -HC = CH; and -CHXW, wherein W can be oxygen, sulfur or NR5; R1 is one to three substituent groups each selected from the group consisting of lower alkyl (C2-Cd), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; R2 is a phenyl group in which said phenyl group is substituted with hydrogen or one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; R3 is hydrogen; Z is selected from the group consisting of carbonyl; carboxyl; carbonylamino or sulfone; R4 is straight or branched chain alkyl having from 2 to 12 carbon atoms; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from substituted or unsubstituted thiophene, furan, pyrrole, or pyridine; and R5 is selected from the group consisting: hydrogen; I rent; cycloalkyl; alkenyl; alkynyl; phenyl, wherein said phenyl group is substituted with hydrogen or one to three substituent groups, each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amido , sulfonamido or nitrile; lower phenylalkyl, wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, carboalkoxy, amino, amino, sulfonamido or nitrile comprising the steps of (1) reacting said compound of formula (XII) with Merrifield resin to form a compound having the formula (XIII): NMe-, N = C = NEt (XII) to obtain a compound having the formula (XIII) (2) reacting said compound of the formula (XIII) with a compound of the formula XIV and an appropriate acid R 4 CO 2 H to obtain a compound of formula (I). 70.- The use of a compound of the formula (I) for the preparation of a medicament for treating inflammatory conditions in a mammal. 71. - A compound according to claim 1, further characterized in that it has the name of N- (2-thiophene) acetyl-2,3,3-triphenylpropylamine. 72. A compound according to claim 1, further characterized in that it has the name of N- (5-methylthiophen) acetyl-2-phenyl-3,3-bis (4-fluorophenyl) propyiamine. 73. A compound according to claim 1, further characterized in that it has the name of N- (3-lndolyl) acetyl-2,3,3-triphenylpropylamine. 74. A compound according to claim 1, further characterized in that it has the name of N-2 (carbonyl-5-methylthiophen) -2 (9H-fluoro-9-yl) -2-phenylethylamine. 75. A compound according to claim 1, further characterized in that it has the name of N- (2-chlorophenyl) acetyl-1,2,2-triphenylcyclopropylmethylamine. 76. A compound according to claim 1, further characterized in that it has the name N- (2-thienyl) carbonyl-1,2,2-triphenylcyclopropylmethylamine. 77. A compound according to claim 1, further characterized in that it has the name of N- (phenyloxy) carbonyl-1,2,2-triphenylcyclopropylmethylamine. 78. - A compound according to claim 1, further characterized in that it has the name of N- (4-chlorophenyloxy) carbonyl-1,2,2-triphenylcyclopropylmethylamine. 79. A compound according to claim 1, further characterized in that it has the name of N- (2-pyridine) acetyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine. 80.- A compound according to claim 1, Also characterized in that it has the name of N- (4-n-butoxyphenyl) acetyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine. 81. A compound according to claim 1, further characterized in that it has the name of N- (2,4-difluorophenyl) acetyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine. 82. A compound according to claim 1, further characterized in that it has the name of N- (2-thiophene) carbonyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine. 83. A compound according to claim 1, further characterized in that it has the name of N- (3-cyanophenyl) acetyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine. 84. A compound according to claim 1, further characterized in that it has the name of N- (2,4-difluorophenyl) carbonyl-2- (3,4-methylenedioxyphenyl) -3,3-d-phenylpropylamine . 85. - A compound according to claim 1, further characterized in that it has the name of N- (4-fluorophenyl) acetyl-2- (3,4-methylenedioxyphenyl) -3,3-d-phenylpropylamine. 86. A compound according to claim 1, further characterized in that it has the name of N- (4,5-dicyorophenyl) carbonyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine. 87.- A compound according to claim 1, also characterized in that it has the name of N- (3-methylphenyl) acetyl-2- (4-trifluoromethylphenyl) -3,3-diphenylpropylamine. 10. A compound according to claim 1, further characterized in that it has the name of N- (phenyl) acetyl-2- (trifluoromethylphenyl) -3,3-diphenylpropylamine. 89. A compound according to claim 1, further characterized in that it has the name N- (5-chloro-2-benzothiophen) acetyl-2- (4-trifluoromethylphenyl) -3,3-diphenylpropylamine . 90. A compound according to claim 1, further characterized in that it has the name of N- (2,4-difluorophenyl) carbonyl- 2- (4-trifluoromethylphenyl) -3,3-diphenylpropylamine. 91. A compound according to claim 1, further characterized in that it has the name of N- (4-trifluoromethylphenyl) acetyl- 2- (4-trifluoromethylphenyl) -3,3-diphenylpropylamine. 92. - A compound according to claim 1, further characterized in that it has the name of N- (phenyl) acetyl-2- (4-trifluoromethyl-phenyl) -3,3-diphenyl-propylamine. 93. A compound according to claim 1, further characterized in that it has the name of N- (4-fluorophenyl) acetyl-2- (4-iodomethyl-phenyl) -3,3-diphenylpropylamine. 94.- A compound according to claim 1, It is further characterized in that it has the name N- (3,5-bis-tri-fluorophenyl) carbonyl-2- (4-iodomethyl-phenyl) -3,3-diphenylpropylamine. 95. A compound according to claim 1, further characterized in that it has the name N- (4-chlorophenyl) carbonyl-2- (4-iodomethyl-phenyl) -3,3-diphenylpropylamine. 96. A compound according to claim 1, further characterized in that it has the name of N- (3,4-dichlorophenyl) carbonyl-2- (4-iodomethyl-phenyl) -3,3-diphenylpropylamine. 97. A compound according to claim 1, further characterized in that it has the name of N- (2-fluorophenyl) carbonyl-2- (4-iodomethyl-phenyl) -3,3-diphenylpropylamine. % 98.- A compound according to claim 1, further characterized in that it has the name of N- (2-fluorophenyl) carbonyl-2- (4-iodomethyl-phenyl) -3,3-diphenylpropylamine. 99. - A compound according to claim 1, further characterized in that it has the name of N- (4-fluorophenyl) carbonyl-2- (4-iodomethyl-phenyl) -3,3-diphenylpropyl amine. 100. A compound according to claim 1, further characterized in that it has the name of N- (4-trifluoromethylfenyl) carbonyl-2- (4-iodomethylene) -3,3-diphenylpropylamine. 101.- A compound according to claim 1, It is further characterized in that it has the name of N- (3,5-bistrifluoromethylphenyl) carbonyl-2- (4-iodomethylphenyl) -3,3-diphenylpropylamine. 102. A compound according to claim 1, further characterized in that it has the name of N- (2-thiophene) carbonyl-2- (4-iodomethyl-phenyl) -3,3-diphenylpropylamine. 103. A compound according to claim 1, further characterized in that it is named N- (5-methyl-2-thiophene) carbonyl-2- (4-iodomethyl-phenyl) -3,3-diphenylpropylamine. 104. A compound according to claim 1, further characterized in that it has the name of N- (4-chlorophenyl) carbonyl-2- (3,4-methylenedioxyphenyl) -3,3-diphenylpropylamine. 105. A compound according to claim 1, further characterized in that it has the name of N- (2-propyl) carbonyl-1, 2,2-triphenylcyclopropylmethylamine.