ARYL AND HETEROARYL COMPOUNDS HAVING ANTI-RETROVIRUS ACTIVITY

Abstract: The present invention relates to a method of treating a retrovirus utilizing a compound of the formula (I): (R2)nR1-Ar-X-Y-R(T1)(T2)m. The present invention also relates to pharmaceutical compositions in which the active ingredient has a compound of formula (I).

Description: ARYL AND HETEROARYL COMPOUNDS HAVING ANTI-RETROVIRUS ACTIVITY I. RELATED APPLICATION This is a continuation-in-part of copending U.S. Application having Serial No. 601,336, which was filed on October 22, 1990. II. FIELD OF THE INVENTION The present invention relates to heteroaryl or aryl containing compounds useful for treating or 10 arresting the progression of a retroviral infection in an animal. Furthermore, the present invention is directed to a method of treating a disease attributable to a retrovirus infection which comprises administering to the animal a therapeutically -*-5 effective amount of an aryl or heteroaryl containing compound. The present invention is also directed to a pharmaceutical composition containing these compounds. III. BACKGROUND OF THE INVENTION Retroviruses contain a (+) RNA genome inside 20 an icosahedral shell. This spherical nucleoprotein core is surrounded by an envelope which consists of a viral encoded glycoprotein molecule in a liquid bilayer which is derived from the plasma membrane of the host. 2 5 The retrovirus infects a host cell by binding to specific receptors on the surface from which it can enter the cell. The viral (+) RNA is uncoated in the cytosol. Reverse transcriptase brought in by the virus particle syntheses both (-) ° and (+) DNA. The DNA genome so synthesized enters the nucleus and becomes integrated in the host cell. 5 - Genomic RNA is formed from the transcription of the DNA, and the RNA is translated to form viral protein. The genome RNA and viral proteins migrate to the plasma membrane and become incorporated into it. A m. portion of the altered membrane builds to form a new retrovirus. The DNA generated from the retrovirus remains in the genome of the infected cell continuing to be expressed. It is even replicated, along with the host DNA. The replicated DNA is then passed on to 0 the daughter cells. Thus, unlike most viral infections, the retrovirus does not rupture or cause the rupturing of a host cell. Retrovirus infections are implicated in a number of diseases, including the Acquired Immune Deficiency Syndrome (AIDS) and the related disease 5 AIDS related complex (ARC) . AIDS and ARC are believed to result from infection by the human immunodeficiency virus (HIV) and antibodies to which are found in the serum of almost all people diagnosed as suffering from 0 AIDS or ARC. Lymphadnopathy-associated virus (LAV) and human T-lymphotrophic virus type III (HTLV-III) as well as related retroviruses have been isolated from a large number of AIDS patients. All of these viruses share important characteristics. HTLV-III and LAV are now believed to be strains of the same virus, which 5 has been given the name Human Immunodeficiency Virus (HIV). AIDS is a disease characterized by loss of cell-mediated immunity and the development of frequent and eventually fatal opportunistic infections. The 0 diagnosis of AIDS is a clinical one, defined as "the occurrence of an illness predictive of a defect in 5 ' _ cell-mediated immunity occurring in an individual with no known cause for diminished resistance of that disease" (Lane, H.C. & Fauci, A.S. Ann. Rev. Immunol. 1985, 3, 477-500). . The use of the term HIV embraces the 5 retrovirus HIV-l or HIV-2 (Human Immunodeficiency Virus Type 1 and Human Immunodeficiency Virus Type 2) , which was discovered in 1983. HIV attacks and reduces the numbers of a subset of white blood cells known as 0 T lymphocytes. Expressed on the cell surfaces of these T lymphocytes is a molecule known as CD4, (such cells are also known as T4 cells). Such lymphocytes, most of which are included in what is functionally defined as the helper/inducer subset, constitute the major proportion of mature T cells. Another major 5 subset of T cells express the CD8 molecule on their cell surfaces (such cells are also known as T8 cells). Most of these are classified as suppressor/cytotoxic cells. Normally the T4/T8 ratio is 1.5 to 2.0. In AIDS patients, however, this ratio is inverted due to a decrease in the absolute numbers of T4 cells, with normal numbers to T8 cells usually being preserved. T4 cells specifically recognize and proliferate in response to antigens that they encounter in the body, at the same time releasing a variety of proteins known as lymphokines that regulate other immune system cells. Upon signaling by T4 cells, B lymphocyte cells recognize antigens and secrete specific antibodies to neutralize or eliminate antigenic bacteria and viruses as they travel through body fluids between cells. Similarly, following signaling from T4 cells, cytotoxic T cells ("T8") become activated to kill cells infected with intracellular pathogens. Furthermore, T4 cells modulate the activities of immune system cells known as natural killer cells and macrophages, which are involved in response to infection and perhaps to incipient malignancies. A critical and early event in HIV infection involves the virus' attachment, via its envelope glycoprotein, to a receptor on the surface of a susceptible T4 cell, the CD4 molecule. The CD4 molecule at the T4 cell surface appears to distinguish potential target cells from HIV and to act as the receptor molecule that binds the virus and allows infection and subsequent viral replication as well as the cytopathic consequences of viral infection. The immunodeficiency of AIDS clearly demonstrates the importance of T4 lymphocytes. Because of the loss of these cells, the remaining T lymphocytes from AIDS patients have diminished or no responses to antigens and show subnormal production of essential immuno-regulatory factors. Because of their decreased numbers and functional capacity, T4 cells are unable to fulfill their necessary role in providing direction for the maturation of B cells and cytotoxic T cells. The ability of AIDS patients to mount antibody reactions to new antigens is severely compromised, though paradoxically high levels of antibodies to previously encountered antigens, including HIV, are often present in patients' sera. At present AIDS and ARC are predominantly found in certain high risk groups such as homosexuals, intravenous drug abusers and those who have received multiple transfusions or products such as Factor VIII derived from blood. Blood donors are now routinely screened for antibodies to HIV and, therefore, future spread of HIV through blood transfusions and blood- derived products should not, hopefully, lead to transmission of AIDS. AIDS is also increasingly found in the heterosexual population. There is increasing evidence that macrophage/monoσyte infection is a vital factor in the 10 persistence and progression of HIV infection, in initiating the brain damage that occurs in AIDS and in triggering the collapse of the immune system as evidenced by eventual profound depletion of T4 lymphocytes. Crowe et al. have demonstrated using - t - anti-HIV p24 antibody that monocyte/macrophages can be infected with HIV. They have demonstrated that up to 70% of cells from individual donors could be infected (AIDS Research and Human Retroviruses, Vol. 3, No. 2, 1987, page 135). Nicholson et al. have proposed an 20 HTLV-III/LAV-induced effect in monocyte function rather than (or in addition to) an intrinsic defect in surviving T cells to account for observed abnormalities in T cell assays that are monocyte- dependent such as pokeweed mitogen-induced Ig synthesis and proliferative responses to soluble 25 antigens. These T cell assays have previously been reported as abnormal even when assayed as T cell subsets (The Journal of Immunology, Vol. 137, No. 1, 1986, page 323) . Since it is well established that the first 30 event that occurs when a foreign material (for example, a virus) enters the body is its uptake by 35 ., mononuclear phagocytes, it is conceivable that these cells represent a primary target for HIV. Gartner et al. have shown that virus production by THLV-III/LAV infected macrophages was high and long-lived, ,- indicating that these cells may play a role in virus dissemination and persistence. They have demonstrated HTLV-III/LAV replication in macrophages was fully productive in the situations they evaluated (Science Vol. 233, 1986, page 215). 10 Salahuddin et al. observed that in vitro pulmonary macrophages can be injected with HTLV-III and appear to be less susceptible to the phytopathic effects of this retrovirus which suggests that tissue macrophages should be considered as potential lt - reservoirs of HTLV-III in vivo (Blood, Vol. 68, No. 1, 1986, page 281) . Ho. D.D. et al. observed normal blood- derived monocytes/macrophages were found to be susceptible to infection in vitro by human T 20 Lymphotropic virus III (HTLV-III), the etiologic agent of the Acquired Immune Deficiency Syndrome. In addition, HTLV-III was recovered from monoσytes/macrophages of patients infected with this virus. It was postulated therefore that HTLV-III 2I - infected monocyte/maσrophages may serve as a vehicle for the dissemination of virus to target organs and as a reservoir for viral persistence, as has been shown for other lentiviruses, including visna virus and caprine arthritis encephalitis virus (J. Clin. Invest, Vol. 77, 1986, page 1712). 30 While an antiviral agent which could kill all infecting HIV or completely inhibit its 35 SUBSTIT , replication (and at the same time have an acceptable toxicity profile) is clearly desirable, the situation heretofore is that no such agent is at present available, c - With the emerging understanding of the role that macrophages may be playing in the pathogenesis of AIDS, it is clear that an effective antiviral strategy will require and approach that can treat infected macrophages and inhibit infection of these cells. 0 Currently the only F.D.A. approved antiviral agents for treatment of AIDS and azido thymidine (AZT) and pentamidine isethionate (PENTAM 300). However, the great majority of these antiviral agents are nucleosides or steroids. But AZT is not completely C - satisfactory. It does not appear to be completely effective at inhibiting macrophage infection or modulating HIV production from infected macrophages. Administration of AZT over long periods of time has been found to give rise to undesirable side effects 0 such as anemia, necessitating blood transfusion, leucopenia and neutropenia. However, unlike the majority of the antiviral compounds, the compounds of the present invention are not nucleosides or steroids. The c compounds of the present invention are much simpler moleucles containing a bridging unit to an aryl or heteroaryl moiety, as described hereinbelow. However, despite their simplicity, the compounds of the present invention are effective in inhibiting retroviruses and 0 particularly the HIV virus. 5 - BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a plot of log (EC 50 ) -:L and σ for diaryl sulfones. Figure 2 is a plot of log (EC so ) -1 and σ for ,_ a subset of diaryl sulfones. Figure 3 is a plot of log (ECso) -1 and R for 2-nitrodiphenylsulfones and its 4-substituted derivatives. Figure 4 is a plot of log (EC so ) -1 and σ for 0 sulfonyl(x), sulfoxides(o) and sulfonate esters(.). SUMMARY OF THE INVENTION The present invention encompasses compounds of the Formula I: (R 2 )n(Rχ) Ar-X-Y-R (T )(T a )m I C - or pharmaceutically acceptable salts thereof, wherein X is S, 0, NH, SO, S0 2 , S0 2 0, S0 2 NG, S-S, 0 Y is a chemical bond or (C a R * )^; R 3 and R-4 are independently hydrogen or lower alkyl; R 5 and R β are independently hydrogen or an electron withdrawing group; G is hydrogen or lower alkyl, aryl, aryl 5 lower alkyl, heterocyclic or heterocyclic lower alkyl; R is an aryl group, lower aryl alkyl, lower alkyl, lower cycloalkyl, lower cycloalkyl lower alkyl, heterocyclic or heterocyclic lower alkyl or the N- oxide of a nitrogen-containing heterocyclic or 0 heterocyclic lower alkyl; 5 SUBSTITUTE SHEET _ T x and T 2 are independently hydrogen or electron donating or electron withdrawing group; R x is an electron withdrawing group; R 2 is hydrogen or lower alkyl or an electron ._ withdrawing group; Ar is aryl or heteroaryl; n and m are independently 0-4; and p is 1-2. The present invention is also directed to __ pharmaceutical compositions containing the compounds of the present invention in association with a pharmaceutical carrier. Furthermore, the present invention is directed to a method of treating retroviral infections, e.g., AIDS, in an animal in need of such treatment by administering to the animal 15 an effective amount of a compound of Formula I. DETAILED DESCRIPTION OF THE PRESENT INVENTION The compound used in the present invention have the formula 0 (R 2 )r_ (Rn.) Ar-X-Y-R-(T 1 )(T 2 ) m wherein R 2 , R x , Ar, Z, X, Y, R, T x , T 2 , n and m are defined hereinabove. In other words, a X=Y group bridges the Ar and R moieties. Ar is an aryl or heteroaryl group. As used herein, when used alone or in 5 combination an "aryl" group is an aromatic group containing from 6 to 14 ring carbon atoms and up to a total of 18 carbon atoms. The aromatic group is planar. It may be monocyclic, bicyclic or polycyclic. If it contains more than 1 ring, the aromatic group is 0 a fused ring system. It includes such groups as 5 - phenyl, naphthyl, phenanthryl, anthryl and the like. The preferred aryl group is phenyl. The term "heteroaryl", when used alone or in combination, is a nitrogen, sulfur or oxygen r - containing heteroaromatic group. The ring hereroatoms 5 are either nitrogen, sulfur or oxygen. The heteroaryl groups may be monocyclic, bicyclic, or polyσyclic; but if it contains more than 1 ring, the rings are fused. Furthermore, the heteroaryl groups are planar. The , 0 heteroaryl groups σontain 1-4 ring heteroatoms and from 5-14 ring atoms. The heteroaryl group σontains from 1-13 and preferably 3-13 ring carbon atoms and up to a total of 18 carbon atoms. The heteroaryl includes such groups as thienyl, benzothienyl, lt - naphthothienyl , thianthrenyl, furyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyrridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, benzoxazolyl; benzoxathiazolyl, 20 benzothiazolyl and benzoisothiazolyl, and the like, and the N-oxides of the nitrogen containing heteroaryl, such as the N-oxides of pyridyl, pyrazinyl, pyrimidinyl and the like. The preferred heteroaryl groups contain up to 10 ring atoms and 1 or 2 ring heteroatoms and up to a total of 15 carbon 25 atoms. Preferably, the heterocyσliσ group σontains at least 1 ring nitrogen atom. Preferred heteroaryl groups inσlude pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, theinyl, furyl, oxazolyl, thiazolyl, 30 benzooxazolyl, imidazolyl, indolyl, quinolyl, isoquinolyl, thiazolyl, benzothiazolyl, benzoxazolyl and pyrrolyl. The especially preferred heteroaryl 35 _ groups include thienyl, pyrazinyl, pyrimidinyl, pyridyl, thiazolyl, and the N-oxide of pyridyl. As defined herein, R is an alkyl group, an aryl group, lower arylalkyl group, lower σyσloalkyl, m. alkyl heterocyclic or heterocyclic lower alkyl or the N-oxide of a nitrogen-containing heterocyclic or heterocyclic lower alkyl. The aryl group defined for R is as defined hereinabove. 10 As defined herein, the "heterocyclic" group, when used alone or in combination, is a nitrogen, sulfur, or oxygen containing heterocyclic group. More specifiσally, the heteroσyσliσ group contains at least 1 ring heteroatom. The ring heteroatoms are either m - oxygen, sulfur or nitrogen and may contain up to four ring heteroatoms. The heterocyσliσ group may be monoσyσliσ, bicycliσ or polyσyclic, but if the heterocyclic group contains more than one ring, the rings are fused. The heterocyclic group contains 1-4 20 ring heteroatoms, from 5-14 ring atoms and from 1-13 and preferably 3-13 ring σarbon atoms and up to a total of 18 carbon atoms. The heterocycliσ groups inσludes the heteroaryl group defined hereinabove and the benzoheterocycliαs. This group also inσludes the fully saturated or partially saturated heterocyclics. 25 The heterocyσlic group includes such groups as those specifiσally enumerated in the preceding paragraph as well as imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, tetrahydrofuryl, morpholinyl and the like. Preferred 30 heterocyclic groups include the preferred heteroaryl groups enumerated above. 5 _ The "alkyl" groups, when used alone or in combination with other groups, are lower alkyl containing from 1 to 6 carbon atoms and may be straight σhain or branσhed. These groups inσlude m. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5 tertiary butyl, pentyl, hexyl, and the like. The preferred alkyl group is methyl. The term σyσloalkyl when used alone or in combination is a σyσloalkyl group σontaining from 3 to 0 18 ring σarbon atoms and up to a total of 25 σarbon atoms. The cycloalkyl groups may be monocyclic, bicycliσ, or polyσyσliσ and if more than 1 ring is present, the rings are fused. The σyσloalkyl group may be σompletely saturated or partially saturated. Examples inσlude σyσlopropyl, σyσlobutyl, σyclopentyl, 5 cyσlohexyl, σyσloheptyl, σyσloσtyl, σyσlodeσyl, cyclohexenyl, σyσlopentenyl, σyσlooσtenyl, σycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl and adamantyl, and the like. The 0 preferred σyσloalkyl is pentyl and hexyl. The "aryl lower aryl" group is an alkyl group whiσh is substituted by an aryl group. Examples inσlude benzyl, phenethyl, phenpropyl, diphenylmethyl, 1,2-diphenylethyl, 1,1-diphenylmethyl and the like. The preferred group is benzyl. 5 The "heteroσyσliσ lower alkyl" group is an alkyl group substituted by a heteroσyσliσ group, as defined and enumerated hereinabove. The "σyσloalkyl lower alkyl' group is an 0 alkyl group whiσh is substituted by a σyσloalkyl group, as defined and enumerated hereinabove. 5 As indiσated hereinabove, the Ar and R groups σan be substituted by an eleσtron withdrawing and eleσtron donating groups. The terms "eleσtron withdrawing" and "eleσtron donating" refer to the ability of a substituent to withdraw or to donate electrons relative to that of hydrogen if the hydrogen atom ocσupied the same position on the oleσule. These terms are well understood by one skilled in the art and are discussed in Advanced Organic Chemistry, by J. March, John Wiley & Sons, New York, New York, pp. 16-18 (1985) and the discussion therein is incorporated herein by reference. Electron withdrawing groups include halo (e.g., bromo, fluoro, chloro, oiodo), nitro, carboxy, lower σarbalkoxy, σarboxa ido, N-loweralkylσarboxamido, N,N-lower dialkyl carboxamido, formyl, lower alkanoyl, lower alkenyl, lower alkynyl, aryl, heterocyσliσ, ammonium, inσluding mono, di-, or tri- alkylammonium, trifluoromethyl, S0 2 CF 3 σyano, sulfonyl, sulfinyl and the like. The preferred electron withdrawing groups are carboxy, ammonium, NO, N 2 " * ~ , S0 2 CF 3 , halo and espeσially nitro. Eleσtron donating groups inσlude such groups as hydroxy, lower alkoxy, including methoxy, ethoxy and the like; amino, lower alkylamino; di(loweralkylamino) ; aryloxy, such as phenoxy, mercapto, lower alkythio, lower alkylmercapto, and the like. One skilled in the art will appreciate that the aforesaid substituents may have eleσtron donating or eleσtron withdrawing properties under different chemical conditions. As defined herein, Y is a chemiσal bond or It is preferred that Y is a σhemiσal bond. EET - However, when p is 1 or 2, it is preferred that R 3 and R 4 are hydrogen or alkyl σontaining 1-3 σarbon atoms. The preferred alkyl group for R 3 and R 4 is methyl. It is espeσially preferred that R 3 and R 4 are hydrogen. ,_ Although p may range from 1-2, the preferred value of p is 1. The preferred value of Ar is phenyl. When Ar is heteroσyσliσ, it is preferred that the ring hetero atom is α to the σarbon atom to whiσh the "X" 0 moiety is bonded. For purposes of this σontext only it is assumed that the 1-position of the heteroσyσlic moiety is that position to which the bridging unit is attached and the α-position is that position in the ring which is adjacent thereto. When Ar is heterocyσliσ, inσluding heteroaryl, it is preferred 5 that the heteroatom is on the α-position of the ring. A nitrogen σontaining heteroaryl σontaining up to 10 ring atoms and two, and preferably one nitrogen ring atom is espeσially preferred. Examples of these 0 heteroaryls inσlude thiazolyl, pyridyl, primidinyl, pyrazinyl, benzoxazoly and the N-oxide of pyridyl. The espeσially preferred value of Ar is phenyl. The preferred value of R is phenyl or heteroσyclic. It is espeσially preferred that R is phenyl. When R is heterocycliσ, however, it is 5 preferred that the ring heteroatom is on the ex¬ position of the ring. The preferred heteroσyσliσ is heteroaryl, espeσially the nitrogen or sulfur- containing heteroaryl group. The preferred heteroaryl contains two, and preferably one ring nitrogen atom or 0 one sulfur ring atom. Examples of the preferred heteroaryl groups for R are thiazolyl, pyridyl. 5 _ pyrimidinyl, pyrazinyl, benzooxazolyl and the N-oxide or pyridyl. The preferred value of X is S0 2 , S0 2 0, CR 5 =CR 6 , SO, S,S-S, HC=CC00H, O H, H, Se0 2 , Se and _- S = N, 5 II o SeO. Espeσially preferred values of X inσlude 0, S = NH II S0 2 0, SO, S0 2 , S, O , and SeO. It is espeσially preferred that X is S0 2 . 0 The preferred value of R^. is nitro or hydrogen, or ammonium. In the σase when Ar is aryl, it is espeσially preferred that Ra. is substituted on the σarbon ring atoms that is α to the bridging group. For example, if Ar is phenyl, it is preferred that R x 5 is in the ortho position. The preferred value of R 2 is hydrogen, lower alkyl, espeσially methyl, σarboxy, σarbalkoxy, halo, espeσially σhloro, nitro σarboxamido and mono, di or tri haloalkyl, espeσially trifluoromethyl. The espeσially preferred value of R 2 is hydrogen or nitro. It is preferred that n is 0, i.e., the only substituent on Ar is R x . It is preferred that Ta. is substituted on the σarbon ring atom that is to the bridging group. The preferred value of T x is hydrogen, lower alkyl or an eleσtron withdrawing group. A more preferred value of T x is hydrogen, nitro, lower alkyl, espeσially methyl, halo, e.g., σhloro, σarboxy, σarbalkoxy, σarboxamide. It is most preferred that T x 0 is hydrogen methyl, σhloro, nitro, nitrosyl, or carboxy. Especially preferred is hydrogen, nitro or σarboxy. The most especially preferred value of T x is hydrogen or nitro. It is preferred that T 2 is an electron withdrawing group, hydrogen or lower alkyl. Preferred values of T 2 are hydrogen, halo, e.g., nitro, chloro, and lower alkyl, e.g., methyl. The preferred value of T 2 is hydrogen. It is preferred that n is O, i.e., the only substituent on R is T x . When either Ar or R is phenyl and any one of T x , T 2 , R x and R 2 are nitro, it is preferred that the nitro substituent is not on the para position of the phenyl. It is preferred that G is lower alkyl, aryl, aryl lower alkyl, heteroσyσliσ or heterocycliσ lower alkyl. An embodiment of the present invention has the formula (R_)« R Ar-X-R(T x )(T 2 ) m wherein R 2 , R x , Ar X, R, T , T 2 , n and m are as defined hereinabove. In a preferred formulation, both Ar and R may eaσh be independently heteroaryl or aryl. In a more preferred embodiment, either Ar or R is phenyl. In the most preferred embodiment, both Ar and R are phenyl. Another embodiment of the present invention has the formulae: wherein R x , R 2 , T x , T 2 , X, n and m are as defined hereinabove. The preferred value of X in these formule are S, SO, or S0 2 and 0 H Especially preferred is s = N SO and S0 2 . The most preferred value of X is S0 2 . It is preferred that n and m are 1 and that R 2 and T 2 are each independently hydrogen or an electron withdrawing group. It is especially preferred that R is nitro, hydrogen or ammonium. Furthermore, if any one R x (R__). T x and (T 2 ) are nitro, it is preferred that the nitro substituent is in the ortho or meta positions. Another embodiment of the present invention has the formula wherein X, R x , R 2 , T x , T 2 , n and m are as defined herein. The preferred values of X in this formula are S, SO and S0 2 and O H. It is preferred that n and m S=N are 1 and R 2 and T 2 are each independently hydrogen or an electron withdrawing group. It is preferred that R x is nitro, hydrogen, or ammonium. Another embodiment of the present invention has the formula wherein R x is H, N0 2 , NH 2 , NH 3 + , NHOH or HO; X is S0 2 , SO or S; T x is H, N0 2 , NH 2 , NH 3 *, NHOH or NO and T 2 is H, CH 3 and OCH 3 . An embodiment of the present invention is wherein R x is H, N0 2 , NH 2 , NH 3 -*-, NHOH or NO, T 2 is H, CH 3 or OCH 3 and X is S0 2 When X is SO, an embodiment of the present invention has the formula wherein R x and T 2 are independently H, N0 2 , NH 2 , NH 3 " * " NHOH and NO and X is SO. Another embodiment of the present invention has the formula wherein T-, , T 2 and more as defined herein. A further embodiment of the present invention has the formula wherein X, R x , R 2 T x and T 2 are as defined hereinabove. In the most preferred embodiment, X is S0 2 , R x , R 2 , T x and T 2 are N0 2 . The present invention contemplates all combinations and permutations of R, R x , T x , T 2 , Ar, R l, n and m as defined herein. The compounds of the present invention can be prepared by art-reσognized methodology using starting materials that are commercially available on readily prepared. For example, compounds of the present invention can be prepared by nucleophile substitution acσording to the following equation: R X (R 2 ) Ar-L + -X-Y R (T x )(T 2 ) m > I II III wherein R x , R 2 , X, Y, R, T x , T 2/ n and m are as defined hereinabove and L is a leaving group, suσh as halogen, e.g., bromo, chloro and the like. A salt, such as potassium ethyl xanthate σan additionally be present to faσilitate the σoupling as, for example, in the σase when Ar is pyridyl. Alternatively, a σompound of Formula I may be formed by reaσting R_.(R 2 ) n Ar-X-L + Y-R(T x )(T 2 ) m > I wherein R x , R 2 , Ar, X, L, Y, R, T x , T 2 , n and are defined hereinabove. For example, when X is S, the - compounds of the present invention can be prepared by reacting a compound of Formula II with -S-Y-R(T X ) (T 2 ) under nucleophiliσ substitution σonditions. The reaction may be run in an inert solvent such as ,_ ethanol, DMF, DMSO, Me 2 SO, or HMPT. The reaction 5 mixture is heated at a temperature sufficient to effeσt the nuσleophiliσ substitution σonditions. The temperature ranges from 50°C to the refluxing temperature of the solvent. As an example, l-nitro-2- 0 (phenylthio)benzene was prepared by reaσting thiophenol in the presenσe of a base with 2- σhloronitrobenzene in hot ethanol. The sulfoxide can be prepared in aσcordance with the procedure desσribed in U.S. Patent No. 4,831,194 to Kriedl et al., whiσh is inσorporated 5 herein by referenσe. More speσifiσally, a sulfinyl halide of Formula IV is reaσted with the σompound of Formula V as shown hereinbelow: (R )(R__)«Ar-SO-Hal + Y-R(T x )(T 2 ) m > I, X=SO 0 IV wherein R x , R 2 , Ar, Y, R, T x , T 2 , n and m are defined hereinabove and Hal is halide. The σompound of Formula IV σan be prepared by reaσting an arylsulfonyl halide (V) with an alkali metal sulfite (MS0 2 ) followed by aσid addition; and halogenating the 5 produσt thereof: (Ri) (R 2 ) n Ar-S0 2 -Hal 1. M 2 SQ 3 R x (R 2 ) n ArSo 2 H V 2. H halogenating agent v IV 0 An exemplary proσedure for the preparation of the sulfonyl σompound is as follows: 5 ( R x ) ( R 2 ) „Ar-Hal + -S0 2 -Y-R(T x ) ( T 2 ),_ _Cu_ > I VI VII where X is So 2 wherein R x , R 2 , Ar, Hal, Y, R, T x , T 2 , n and are as defined hereinabove. The aryl halide (VI) is reaσted with the sulfonate (VII) in the presence of a copper catalyst. The reaction mixture is heated at temperatures ranging from 50-250°C, and preferably at about 180°C, to form the produσt. Alternatively, the sulfoxide and the sulfones σan be prepared from the σorresponding thiols. For example, one mole of the compound of Formula I wherein X is S is reacted with one mole of an oxidizing agent, such as 30% H 2 0 2 , NAIO * , t-BuO-Cl, acyl nitrite, peracids, sodium perborates and the like, to form the corresponding sulfoxides. The sulfoxide in turn can be further oxidized to the corresponding sulfones by reacting the sulfoxide with another mole of an oxidizing agent, such as 30% H 2 0 2 , KMnO-4, potassium hydrogen persulfate, sodium perborate and the like, to form the corresponding sulfone. If excess oxidizing agent were present, then the sulfide σan be direσtly σonverted to the sulfone without isolation of the sulfoxide. The sulfonic aσid ester σan be prepared by reaσting the halide of Formula II, i.e., where L is halide and R x , R 2 , Ar and n are as defined herein with (t x ) (t 2 ) ιrι R-Y-S0 3 _ under nuσleophiliσ substitution σonditions as desσribed herein. Alternatively, the sulfoniσ ester σan be prepared by reaσting the sulfonyl halide of Formula VIII with an alσohol (or phenol) of Formula IX under esterifiσation σonditions χ ( R x ) ( R 2 ) Ar-S0 2 Cl + HO-Y-R( T x ) ( T 2 ) m > I VIII IX The selenium σompounds, i.e., σompounds in whiσh X is Se, SeO, Seo 2 , or Se0 3 , σan be prepared in r - an analogous fashion to the σorresponding sulfur compounds, i.e., S, SO, S0 2 or S0 3 , respectively, that are described herein. An exemplary procedure for preparing amine compounds in which X is NH is by reacting a compound 0 of Formula II wherein L is a halo, suσh as bromo or σhloro, with H 2 N-Y-R(T X ) (T 2 ) m in the presenσe of a base, such as sodium carbonate, and optionally in the presence of a copper catalyst. Compounds in which X is O can be prepared by the following exemplary procedure. The salt of an 5 alcohol (or phenol) of Formula X is reacted with the compound of Formula II wherein L is halo, e.g. bromo or chloro under nuσleophiliσ substitution reactions. II + -0-Y-R(T x )(T 2 ) n >I 20 An exemplary procedure for preparing a sulfonamide, i.e., σompounds in which X is S0 2 NH 2 is by reaσting a sulfonyl halide of the formula V, e.g. where Hal is σhloro, with an amine of the formula H 2 N-Y-(R) (T x ) (T 2 ) under substitution reaσtion ._ conditions. H 25 I The compounds in which X is S = N σan be O prepared by techniques known to one skilled in the art. an exemplary proσedure is as follows. Oxidation of the sulfoxide prepared 30 hereinabove with hydrazoiσ aσid (HN 3 ) generate the σompound of the present invention in whiσh 35 1 X is S = NH. Alternatively, the sulfoximine o (σompounds of the present invention in whiσh X is S = NH) are prepared by oxidizing the σorresponding sulfinimine (S = NH) with hydrogen peroxide. As in many organiσ reaσtions, inert solvents in the above reaσtions σan be employed such as 10 methanol, ethanol, propanol, acetone, tetrahydrofuran, dioxane, dimethylforma ide, diσhloromethane, σhloroform, and the like. The reaσtions are normally effeσted at or near room temperature, although temperatures ranging from 50°C up to the reflux τ_5 temperature of the reaσtion mixture σan be employed. The various substituents on the σompounds, e.g. as defined in R x , R 2 , T x and T 2 can be present in the starting compounds, added to any one of the intermediates or added after formation of the final 2o products by the known methods of substitution or conversion reactions. For example, the nitro groups can be added to the aromatic ring by nitration and the nitro group converted to other groups, suσh as amino by reduσtion, and halo by diazotization of the amino 25 group and replaσement of the diazo group. Alkanoyl groups σan be substituted onto the aryl groups by Friedel-Crafts acylation. The acyl groups σan be then transformed to the σorresponding alkyl groups by various methods, inσluding the Wolff-Kishner reduσtion Q and Clemmenson reduσtion. Amino groups can be alkylated to forir. mono, dialkylamino and trialkylamino groups; and mercapto and hydroxy groups can be 35 alkylated to form σorresponding thioethers or ethers, respeσtively. Primary alσohols σan be oxidized by oxidizing agents known in the art to form σarboxyliσ aσids or aldehydes, and secondary alcohols can be oxidized to form ketones. Thus, substitution or alteration -reaσtions can be employed to provide a variety of substituents throughout the molecule of the starting material, intermediates, or the final produσt. In the above reactions, if the substituents themselves are reactive, then the substituents can themselves be protected acσording to the teσhniques known in the art. A variety of protecting groups known in the art may be employed. Examples of many of these possible groups may be found in "Protective Groups in Organic Synthesis," by T. W. Greene, John Wiley & Sons, 1981. Resulting mixtures of isomers can be separated in the pure isomers by methods known to one skilled in the art, e.g., by fraσtional distillation, σrystallization and/or σhromatography. The aσtive ingredients of the therapeutiσ σompositions and the σompounds of the present invention exhibit exσellent anti-retrovirus aσtivity when administered in amounts ranging from about 10 mg to about 100 mg per kilogram of body weight per day. a preferred dosage regimen for optimum results would be from about 20 mg to about 50 mg per kilogram of body weight per day, and suαh dosage units are Q employed that a total of from about 1.0 gram to about 3.0 grams of the aσtive σompound for a su jeσt of about 70 kg of body weight are administered in a 24- 5 hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response and is preferably administered one to three times a day in dosages of about 600 mg per administration. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practiσal advantage is that the active compound may be administered in a convenient manner such as by the oral, intravenous (where water soluble) , intramuscular or subcutaneous routes. The active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutiσ administration, the aσtive compound may be incorporated with excipients and used in the form of ingestible tablets, bucσal tablets, troσhes, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may convietly be between about 5 to about 80% of the weight of the unit. The amount of aσtive σompound in such therapeutically useful σompositions is suσh that a suitable dosage will be obtained. Preferred σompositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 5 and 1000 mg of active compound. The tablets, troches, pills, capsules and the like may also σontain the following: A binder suσh as gum tragaσanth, aσaσia, σorn starσh or gelatin; exσipients suσh as diσalσium phosphate; a disintegrating agent suσh as σorn starσh, potato starσh, alginic aσid and the like; a lubriσant suσh as magnesium stearate; and a sweetening agent such as sucrose, lactose or saσσharin may be added or a flavoring agent suσh as peppermint, oil of wintergreen, or σherry flavoring. When the dosage unit form is a σapsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be σoated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of σourse, any material used in preparing any dosage unit form should be pharmaσeutiσally pure and substantially non-toxiσ in the amounts employed. The aσtive compound may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glyσerol, liquid polyethylene glyσols, and mixtures thereof and in oils. Under ordinary σonditions of storage and use, these preparations σontain a preservative to prevent the growth of miσroorganisms. The pharmaσeutiσal forms suitable for injeσtable use inσlude sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injeσtable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like) , suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a σoating suσh as lecithin; by the maintenance of the required particle size in the case of dispersion and by the use of surfaσtants. The prevention of the action of microorganisms σan be brought about by various antibaσterial and antifungal agents, for example, parabens, σhlorobutanol, phenol, sorbiσ aσid, thimerosal, and the like. In many σases, it will be preferable to inσlude isotoniσ agents, for example, sugars or sodium σhloride. Prolonged absorption of the injeσtable σompositions σan be brought about by the use in the σompositions of agents delaying absorption, for example, aluminum monostearate and gelatin. sterile injeσtable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which σontains the basiσ dispersion medium and the required other ingredients from those enumerated above. In the σase of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique whiσh yield a powder of the aσtive ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof. As used herein, "pharmaσeutically acσeptable σarrier" inσludes any and all solvents, dispersion media, σoatings, antibaσterial and antifungal agents, isotoniσ and absorption delaying agents, and the like. The use of suσh media and agents for phar aσeutiσal active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients σan also be incorporated into the compositions. It is especially advantageous to formulate parenteral σompositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physiσally discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calσulated to produσe the desired therapeutiσ effeσt in assoσiation with the required pharmaσeutiσal σarrier. The speσifiσation for the novel dosage unit forms of the invention are diσtated by and direσtly dependent on (a) the unique σharaσteristiσs of the aσtive material and the partiσular therapeutiσ effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail. The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acσeptable σarrier in dosage unit form as hereinbefore disclosed. A unit dosage form can, for example, contain the principal active compound in amounts ranging from about 5 to about 1000 mg, with from about 250 to about 750 mg being preferred. Expressed in proportions, the active compound is generally present in from about 10 to about 750 mg/ml of carrier. In the σase of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients. For a better understanding of the present invention together with other and further objects, reference is made to the following descriptions and examples. These examples are provided solely for illustrative purposes. Therefore, the invention is not to be limited in any way by the exemplification. EXAMPLE 1 l-nitro-2-(phenylthio)benzene The following proσedure served as the model for the formation of all σompounds of this type required by this study. 2-Chloronitrobenzene (25.0 g, 0.16 mol) in 80 ml of hot ethanol was added to a mixture of thiophenol (17.60 g, 0.16 mol), Na 2 Co 3 (20.8 g, 0.224 mol), and 70 ml of H 2 0 and the whole was stirred and heated to boiling for 2 h. The reaσtion mixture was then poured into 275 ml of iσe- water to preσipitate a dark yellow solid. The σrude l-nitro-2-(phenylthio)benzene, mp 76-78°C, was reσrystallized from 95% ethanol to afford 33.3 g (90%) of bright yellow σrystals, mp 78.5 -80°C (lit. mp 78- 80°C). IR (KBr) 1500 and 1334 σπT 1 (N0 2 ); ^H NMR (CDCL 3 ) 8.5 (m, 1 H), 7.35 (m, 7 H) and 6.75 (m, 1 H) . S EXAMPLE 2 1-[ (4-Methylpheny1)thio]-2-nitrobenzene This compound was prepared by the model procedure from the following compounds: 4- Methylthiophenol (12.40 g, 0.10 mol), Na 2 Co 3 (14.80 g, 0.14 mol), and 2-chloronitrobenzene (15.7 g, 0.10 mol) . The σrude product, p 85-87°C, was recrystallized from alσohol to afford 22.30 g (91%) of brillant yellow needles, mp 89-90°C (lit. mp 89-90°C) . IR (KBr) 3062 (C-H), 1510 and 1334 (N0 2 ), and 1458 σm "1 (CH 3 ); X H NMR (CDC1 3 ) 6 8.15 (m, 1 H), 7.25 (m, 6 H), 6.75 (m, 1 H) and 2.35 (s, 3 H) . EXAMPLE 3 l-[ (4-Chlorophenyl)thio]-2-nitrobenzene This σompound was synthesized by the model proσedure from the following σompounds: 4- Chlorothiophenol (15.0 g, 0.10 mol), Na 2 C0 3 (15.50 g, 0.15 mol), and 2-σhloronitrobenzene (16.3 g, 0.10 mol). The σrude produσt, mp 91-93°C, was reσrystallized from alσohol to afford 25.0 g (91%) of yellow σrystals, mp 94-95°C (lit. mp 94°C) . Ir(KBr) 3050 (C-H), 1512 and 1336 σπTl (N0 2 ); ^H NMR (CDC1 3 ) δ 8.2 (m, 1 H) and 7.45 (m, 7 H) . EXAMPLE 4 l-Nitro-2-(phenylsulfonyl)benzene (1). The following procedure served as the model for all compounds of this type required by this study. 1- Nitro-2- (phenylthio)benzene (6.50 g, 28.0 mmol) was added to 40 ml of acetic acid in a flask equipped with a magnetic stirrer. The mixture was heated to 90°C. To the stirred, warm aceticc acid solution, 12.5 ml (0.12 mol) of 30% hydrogen peroxide was added slowly over a 15-min period. After 1 h at 90°C, the reaction mixture was heated to boiling and water was added until the solution became turbid. The solution was cleared by adding acetiσ aσid and then σooled slowly to room temperature. The white needles that crystallized were separated by suction filtration and allowed to dry. The yield of l-nitro-2- (phenylthio)benzene was 7.05 g (95%), mp 145-146.5°C (lit. 49 mp 146-147°C). IR (KBr) 3085 (C-H), 1547 and 1320 (N0 2 ), and 1319 and 1157 cm -1 (S0 2 ); ^H NMR (CDC1 3 ) δ 8.2 (m, 1 H) and 1.65 (m, 8 H) . EXAMPLE 5 1-(4-Methylphenylsulfonyl)-2-nitrobenzene (2) . This compound was prepared by the model proσedure from l-[ (4-methylphenyl)thio]-2-nitrobenzene (7.00 g, 29.0 mmol), 30% H 2 0 2 (12.0 mL, 0.12 mol), and 50 mL of aσetiσ aσid. The yield of nitrosulfone was 7.20 g (91%), mp 155-156°C (lit. mp 156-157°C). After several weeks of storage in a σlear glass bottle, the sulfone turned light green. IR (KBr) 3085 and 2950 (C-H), 1546 and 1322 (N0 2 ), 1320 and 1158 σm" 1 (S0 2 ); *__ NMR (CDC1 3 δ 7.75 (m, 8 H) and 2.4 (s, 3 H). SUBSTITUTESHEET EXAMPLE 6 1-(4-Chlorophenylsulfonyl)-2-nitrobenzene (36). This σompound was prepared by the model proσedure from l-[(4-σhlorophenyl)thio]-2-nitrobenzene (7.00 g, 26.0 mmol), 30% H 2 0 2 (11.0 mL, 0.11 mol), and 40 mL of aσetiσ aσid. The yield of sulfone was 7.00 g (90%), mp 136.5-137.5°C (lit. p 137-138°C) . IR (KBr) 3087 (C-H), 1543 and 1324 (N0 2 ), 1318 and 1159 σπT 1 (S0 2 ; X H NMR (CDC1 3 ) δ 8.15 (m, 1 H) and 7.6 (m, 7 H). EXAMPLE 7 Using the proσedures desσribed herein, the following σompounds σan be prepared: *Pyridine rings with N at position R a SUBSTITUTESHEET EXAMPLE 8 Other σompounds σan be prepared by the proσedures desσribed herein: SUBSTITUTE SHEET EXAMPLE 9 Bis(o-nitrophenyl) Disulfide. —To a warm solution of 55 g of Na 2 S - 9H 2 0 in 55 mL of water were added 145 mL of 95% ethanol and 6.41 g of powdered sulfur. Heating and stirring were continued until the sulfur dissolved. The filtered two-phase liquid was added in portions with stirring to 55 g of o- σhloronitrobenzene in 80 mL of 95% ethanol. After the initial vigorous reaσtion, the very dark brown reaσtion mixture was heated with stirring on the steam bath for 3 h. The mixture, now a yellow solid in a reddish liquid, was σooled to room temperature and filtered. The solid was suspended in 200 L of water, stirred 0.5 h, filtered off, and pressed on the filter. The filter σake was broken up, washed with 35mL of 95% ethanol), and pressed on the filter. The filter σake was broken up and dried in air. There resulted 28.5 g (53%) of yellow powder melting at 195.5-197.0°C to a dark liquid. Crystallization of 1 9 of the σrude material from 28 mL of glaσial acetic aσid gave 0.87 g of bright yellow furσated needles melting at 197.5-199.0°C to a yellow melt. The σompounds of the present invention are effeσtie in treating diseases attributable to retroviruses suσh as AIDS or ARC in animals, suσh as mammals. These σompounds are σapable of retarding the progression of retroviruses. Further, they are σapable of retarding the growth and/or repliσation of the retrovirus. These σompounds are believed to retard the progression of the retrovirus infeσtions attributable to HTLV-1, HTLV-2 or Lentivirus. Inσluded in the σlass of Lentivirus in whiσh σompσunds of the present invention are extremely effeσtive are HIV-l, HIV-2, SIV or medi-vesni. Thus, σompounds of the present invention are useful in treating AIDS or AIDS related σomplex (ARC) and to ameliorate or improve the σondition in the animal affliσted with the retrovirus. To determine the effeσtiveness of the σompounds of the present invention, various assays, approved by the N.C.I, have been developed. One suσh method is used to determine the effeσtiveness of representative σompounds and σompositions of the present invention in the Rausσher and LP-BMS Murine Leukemia Virus (MLV) In Vitro Assays. In aσσordanσe with the proσedure, SC-1 σells were grown as monolayers in 6-well tissue σulture plates (Falσon) . The a test σompound was added to the σultures at the time of virus inoσulation (approximately 24 hours after the σells were seeded) and was present for 3 days, at whiσh time the σultures were irradiated with UV light. All σompounds were solubilized in DMSO prior to dilution in grown medium. The highest σonσentration of DMSO present in the σultures was 0.05%. The test σultures (tripliσate σultures per drug σoncentrate) eaσh σontained 2 ml of test σompound diluted in growth medium (Eagle's minimum) essential medium (EMEM) supplemented with 5% heat-inaσtivated fetal bovine serum (FBS) and 0.5ml of the virus suspension diluted to produσe a σountable number of plagues per well. The six virus σontrol σultures σontained 2ml of medium and 0.5ml of the - virus suspension. NSC606170(ddC) was inσluded as a positive σontrol drug. Drug σytotoxiσity σontrol σultures (σontaining test σompound) but no virus and cell control σulture (σontaining no test compound) or virus were inσluded in the assay. On day 3 post-virus inoσulation, the σultures were irradiated and XC σells were added. Three days after V-irradiation, the σultures were fixed with formalin and stained with 0.1% σrystal violet. The plaques were σounted with the aid of a disseσtion miσroscope. A dye conversion assay to determine drug- induced cytotoxiσity was performed. This assay is based on the σonversion of MTT to a formazan produσt in living σells. This conversion results in a color change which can be detected speσtrophotometriσally. A 96-well tissue σulture plate was seeded with 1.4X10 SC-1 cells per well at the time that the 6-well plates were seeded for the UV-XC plaque assay. The following day, the medium was decanted and the cell control cultures received 100 ul of medium. The drug σontrols reσeived 80ul of drug and 20ul of medium such that the final concentration of drug was equivalent to that used in the 6-well plates. On day 3 after addition of the drug, 50ul of a 2mg/ml soltution of MTT in EMEM with 5% heat-inactivated FBS were added to each well. The culture was incubated for 7 hours and lOOul of a 10% SDS: 0.01 N HCL solution was added to each well. The culture was incubated overnight and the following morning the optical density (O.D.) was read at 570nm wavelength on a Perkin-Elmer speσtrophoto eter. The perσent reduσtion in the drug-treated σell O.D. reading σompared to the σontrol σell O.D. reading was σalσulated. Using the proσedure, the following data is generated from representative σompounds of the present invention. i. Data from Rausσher MuLV assay Data from Formazon assay: Test Compound 1 Test Compound 2 Compound 37 = Compound Conσentration Virus Control 11. Data from LP-BM5 MuLV assay Test Compound 1 #3 Count Reduction T T 328 254 11% 232 261 9% 210 255 11% 228 207 27% 311 246 14% Test Compound 2 111. Data from Cytotoxiσity Assay Test Compound 1 Compound Conσentration 1X10 "3 M IXIO" 4 M IXIO" 5 M IXIO" 6 M ixio- "7 M none Test Compound 2 Another assay for testing the effiσaσy of the σompounds is the procedure * used in the National cancer Institute's test for agents active against Human Immunodeficienσy Virus (HIV) . It is designed to deteσt agents aσting at any stage of the virus reproduσtive σycle. The assay basically involves the killing of T4 lymphocytes by HIV. Small amounts of HIV are added to cells, and a complete cyσle of virus reproduσtion is neσessary to obtain the required σell killing. Agents that interaσt with virions, σells, or virus gene-produσts to interfere with viral aσtivities will proteσt σells from σytolysis. The system is automated in several featues to accommodate large numbers of candidate agents and is generally designed to detect anti-HIV activity. However, compounds that degenerate or are rapidly metabolized in the σulture σonditions may not show aσtivity in this sσreen. All tests are σompared with at least one positive (e.g. AZT-treated) σontrol done at the same time under identiσal σonditions. * eislow, O.W., Kiser, R. , Fine, D. , Bader, J. , Shoemaker, R.H. , Boyd, M.R. : New soluble-formazan assay for HIV-l σytopathiσ effeσts: appliσation to high-flux sσreening of synthetiσ and natural produσts for AIDS-antiviral aσtivity. J. Natl. Canσer Inst. 81:577-586, 1989. The proσedure is as follows: 1. The Candidate agent is dissolved in dimethyl sulfoxide (unless otherwise instruσted) then diluted 1:100 in σell σulture medium before preparing serial half-logo 1D dilutions. T4 lymphocytes (CEM cell line) are added and after a brief interval HIV-l is added, resulting in a 1:200 final dilution of the compound. Uninfected σells with the σompound serve as a toxicity control, and infected and uninfected cells without the compound serve as basic controls. 2. Cultures are incubated at 37° in a 5% carbon dioxide atmosphere for 6 days. 3. The tetrazolium salt, XTT, is added to all wells, and cultures are incubated to allow formazan color development by viable cells. 4. Individual wells are analyzed spectrophotometriσally to quantitate formazan produσtion, and in addition are viewed miσroscopically for detection of viable cells and confirmation of protective activity. 5. Drug-treated virus-infected cells are compared with drug-treated noninfeσted σells and with other appropriate σontrols (untreated infected and untreated noninfected cells, drug-containing wells without cells, etc.) on the same plate. 6. Data are reviewed in comparison with other tests done at the same time and a determination about activity is made. The results on representative compounds are given hereinbelow: IN-VITRO TESTING RESULTS - COMPOUND 1 CELL LINE: CEM-V BSTITUTE SHEET IN-VITRO TESTING RESULTS - COMPOUND 1 CELL LINE: CEM-Z -SO- IN-VITRO TESTING RESULTS - COMPOUND 1 CELL LINE: CEM-V IN-VITRO TESTING RESULTS - COMPOUND 1 CELL LINE: CEM-Z IN-VITRO TESTING RESULTS - COMPOUND 1 CELL LINE: CEM-V IN-VITRO TESTING RESULTS - COMPOUND 1 CELL LINE: CEM-V IN-VITRO TESTING RESULTS - COMPOUND 6 CELL LINE: CEM-IW IN-VITRO TESTING RESULTS - COMPOUND 6 CELL LINE: CEM-IW IN-VITRO TESTING RESULTS - COMPOUND 6 CELL LINE: CEM-IW IN-VITRO TESTING RESULTS - COMPOUND 6 CELL LINE: CEM-IW Additional results are summarized hereinbelow. τ 2 H H Me Cl H H H H "Pyridine ring with the N at position R α . Obviously, there is a structure activity relationship with respect to the efficacy of the compounds of the present invention. Factors that affect the relationship may include steric effects, electronic effects, (electron withdrawing or electron donating ability), resonance effects, hydrophobic, hydrophilic, hydrogen bonding parameters, etc. The data in the tables suggest certain trends: (a) An o- nitro group on diphenyl sulfone increases anti-HIV activity, (b) A pOnitro group on diphenyl sulfone increases cytotoxicity and appears to render the 6683 ■ 59- compound undesirable as a chemotherapeutic agent, (c) an amino group ortho or para on diphenyl sulfone administer anti-HIV activity. Thus, these trends suggest a relationship between the structure of the σompound and its activity or EC so , i.e. the concentration of active compound to reduce the retroviral concentration by 50%. Based on the data, it has been determined that there is a direct correlation between the log (ECso) -1 and the elecctronic effet of a substituent (σ) or more precisely the sum of the sigma (σ) values. (The greater the electron withdrawing ability of a substituent, the higher the value of σ, while a better electron donating group has a lower value of σ. ) There appears to be a direct correlation between log (ECso) -1 and the ∑σ; as the ∑σ increases, so does the log (EC 50 ) ~ . The addition of substituents to the diphenyl sulfone will affect the factors discussed hereinabove, thus both the log (EC 50 ) -1 and the ∑σ will be affected. Thus for the diphenyl sulfone derivative the relation is (log EC 50 ) 1.039 Σ + 4.415 EQ1 This relationship is a linear correlation between ∑σ and (log EC 5 o) _1 . (See Figure 1). Furthermore, this relationship quantities anti-HIV activity with sigma values and hence with electrons donating or withdrawing power of various groups, the latter type of group enhancing anti-HIV activity. The σ values may range from -4.00 to +4.00. It is preferred that the σ values range from -1/00 to 4.00. Two developmental suggestions follow from the relationship. One is that the anti-HIV activity of 2-nitrodiphenyl sulfone may be augmented by the introduction of additional electron-withdrawing groups. In part, this suggestion is strengthened by the increased potency of 2,2'-dinitrodiphenyl sulfone. Another developmental suggestion is that, in 2-nitrodiphenyl sulfone, the nitro group itself might be replaced by different electron-withdrawing groups with the result that the modified compound may yet show anti-HIV activity. In 2-nitrodiphenyl sulfone, for example, the nitro group may be replaceable by CN, NO, and other groups with large positive σ 0 values. Although few reliable values for σ 0 are available, it has been noted that the σ 0 values are approximated by σp values, and suitable replacement candidates may be chosen on the latter basis. Encouragement is afforded by aza situation wherein the o-nitrophenyl unit is replaced by the 2-pyridyl unit: phenyl 2-pyridyl sulfone shows anti-HIV activity. The compounds of the correlation can be subdivided into two intersecting subsets. The first of these subsets includes diphenyl sulfone and its 2- amino-, 2-nitro-, 2,2'-dinitro-derivatives. There the potencies span two powers of the ten in the correlation log(EC BO )- χ = 1.07∑σ + 4.419 (n=4; r=0.994) Although the attached groups are structurally very restricted, they embrace extremes from a strong electron-donor (NH 2 ) to a strong electron-withdrawing group (N0 2 ) . (See Figure 2) . The 4'-substituted-2-nitrodiphenyl sulfones constitute the second subset. Their data points account for much of the scatter in the larger linear relationship. The 4'-substituents (cl, H, Me, MeO) vary from a mildly electron-withdrawing group to a strongly electron-releasing group. Although log (ECso) ""3 - for those points over their very limited range do not correlate well with either σ or σ- (r>0.7), they correlate somewhat better with σ ~ * " ; log(EC so )- = 0.558σ + 5.346 (n=4; r=0.919). Better still is a correlation with r x , the resonance component of the substituents' σ value (Figure 3). log(EC so )- = 1.018R X + 5.445 (n=4; r=0.984). The developmental suggestion here is that greater potency may be achieved by adding onto the 2- nitrodiphenyl sulfone skeleton groups with large positive R-values. Two sulfoxides and two sulfonate esters also show moderate activity in 0 anti-HIV assays. Interestingly, if the points for their respective values for log(EC 50 ) -x and ∑σ for their aromatic ring substituents are plotted on the same graph with the sulfones, they fall very close to the correlation line (Figure 4). When the results are included in the sulfone correlation, a new correlation emerges which is nearly identical with the correlation for the sulfones alone: log(EC 50 )- = 1.043∑σ + 4.433 (n-11; r=0.977) The implication of this extended correlation is that the unit linking the aromatic rings is open to some variability; the -S0 2 -, -SO-, and -S0 2 0- bridges appear to be equivalent. However, the bridging unit has structural limitations. Two moderately active sulfides (with the -S-bridge) provide points which do not appear to be collinear with the correlation line. Thus, while the invention has been described with reference to certain preferred embodiments, those skilled in the art will realize that changes and modifications may be made thereto without departing from the full and intended scope of the appended claims.

Claims: WHAT IS CLAIMED IS: 1. A pharmaceutical composition for the treatment of retrovirus infection comprising a therapeutically effective amount of a compound of the formula: (R 2 )n(R x ) Ar-X-Y-R (T:,.)(T 2 ) ιn or pharmaceutically acceptable salts thereof wherein: H H I I X is S, O, N, SO, S0 2 , S0 2 0, S0 2 NG, S=N, 0 C = C , S-S, Se0 2 , SeO or Se; R 5 R β Y is a chemical bond or (CR 3 R 4 )p; R 3 and R 4 are independently hydrogen or lower alkyl; R s and R 6 are independently hydrogen, lower alkyl or an electron withdrawing group; R is an aryl group, lower arylalkyl, lower alkyl, lower cycloalkyl, lower cycloalkyl lower alkyl, heterocyclic or heterocyclic lower alkyl or the N- oxide of a nitrogen-containing heterocyclic or heterocyclic lower alkyl; G is hydrogen, lower alkyl, aryl, aryl lower alkyl, heterocyclic, or heterocyclic lower alkyl, o. and T 2 are independently hydrogen or electron donating or electron withdrawing group; R x is an electron withdrawing group; R z is hydrogen or lower alkyl or an electron withdrawing group; Ar is aryl or heteroaryl; n and m are independently 0-4; and p is 1-2 with the proviso that neither Ar (Rι)(R 2 ) n nor R ( iJlT a Jπ, is an unsubstituted or substituted 4-nitrophenyl. 2. The composition according to Claim 1 in which the compound has the formula: (R 2 ) n (Rx) Ar-X-R ( T ) ( T s ) m 3. The composition according to Claim 1 or 2 in which the σompound has the formula or R, τ π 4. The composition of Claim 1 wherein the compound is of the formula: wherein m is 0-4 and o. is hydrogen or electron withdrawing group; T and T 2 are hydrogen, electron withdrawing or electron donating groups, such that the sigma values of R x , T x and T 2 are related to EC so by the following equation: log(EC so ) ~ = 1.039∑σ + 4.415, wherein o ranges from -4.00 to 4.00 and EC 50 is 50% effective concentration. 5. The composition according to Claim 4 in which o ranges from -1.00 to 4.00. 6. The composition according to Claim 1 in which the compound has the formula m and the s gma values to T x and T 2 are defined by the equation: log (ECso) -1 = 1.070Σ0 + 4.419, wherein o = -4.00 to 4.00. 7. The composition according to Claim 1, wherein the compound has the formula: wherein X is S0 2 , SO or S; H R is H, N0 2 , NH 2 , NH 3 -, NOH, or NO; T x is H, N0 2 , NH 2 , NH a -4 -, NOH, or NO and H T 2 is H, CH 3 or 0CH 3 . 8. The method according to Claim 7 in which X is S0 2 or SO. 9. The composition aσcording to Claim 1 or 2 in which Ar is aryl or heteroaryl. 10. The composition according to any of Claims 1 to 9 in which R is on the σ-carbon position. 11. The composition according to Claim 10 in which R x is nitro. 12. The composition acσording to Claim 9 in whiσh the heteroatom is nitrogen. 13. The σomposition aσcording to Claim 1 or 2 in which R is aryl. 14. The composition acσording to any of Claims 1 to 3 in whiσh T x is on the σ-position. 15. The σomposition aσσording to Claim 14 in whiσh T x is nitro. 16. The composition according to Claim 1 or 2 in which R is heteroaryl. 17. The composition according to Claim 16 in which the heteroatom is on the σ-position. 18. The composition according to Claim 1 or 2 in whiσh Ar and R are independently phenyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzoxazolyl, or the N-oxide of pyridyl. 19. The σomposition aσσording to any of Claims 1 to 18 in whiσh X is S0 2 , S-S, S, SO, S0 2 0, S, H H I O, N, S=N, or SeO. O 20. The σomposition aσσording to Claim 19 H I in whiσh X is S0 2 , SO, S0 2 0, or S=N 0 21. The σomposition aσcording to any of Claims 1 to 20 in which T x and T 2 are independently hydrogen or an eleσtron withdrawing group. 22. The composition according to any of Claims 1 to 21 in which Y is methylene. 23. The composition acσording to any of Claims 1 to 22 in whiσh R x and T x are independently sulfonyl, sulfinyl, nitro, hydrogen, σyano, σarboxyl, trifluoro ethyl, S0 2 CF 3 , nitrosoyl or ammonium. 24. The σomposition aσσording to Claim 23 in whiσh R 2 and T 2 are independently nitro, hydrogen, methyl or halo. 25. The pharmaσeutiσal σomposition aσσording to Claim 1 in whiσh the σompound has the formula: wherein X is S0 2 , SO or S . 26. A σompound as desσribed in any of Claims 1 to 25 for use in preparing a pharmaσeutiσal σomposition useful in treating a retrovirus infeσtion. 27. A σompound aσσording to Claim 26 in whiσh the retrovirus is at least one of the viruses seleσted from HTLV-1, HTLV-2, HIV-l, HIV-2, SIV or medi-visna.

Inventors: WASSMUNDT FREDERICK W, WASSMUNDT, FREDERICK, W.
Applicants: RES CORP TECHNOLOGIES INC, RESEARCH CORPORATION TECHNOLOGIES, INC.
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, C07C309, C07C317, C07C323, C07C381, C07C391, C07D213, C07D277, C07D335