ITTO20010950A1 - INSULIN RECEPTOR ACTIVATORS FOR THE TREATMENT OF METABOLIC DISORDERS IN HUMAN BEINGS RESULTING FROM THE TREATMENT OF INFECTIONS FROM - Google Patents

Description

DESCRIPTION of the industrial invention entitled: "Insulin receptor activators for the treatment of metabolic disorders in humans resulting from the treatment of HIV infections with HIV protease inhibitors",

DESCRIPTION

BACKGROUND OF THE INVENTION

(a) Field of the invention

The present invention relates to processes, chemical compounds and compositions for the treatment of diseases induced by the use of an HIV protease inhibitor. In particular, the invention relates to methods, compounds and compositions for the treatment of metabolic disorders induced by HIV protease inhibitors.

(b) Description of the related technique

Treatment of HIV infection has been shown to be very effective in controlling the damage of the end-stage AIDS infection. HIV protease inhibitors are an extremely important component in drug regimens used to suppress viral load and the resulting symptoms of AIDS. Unfortunately, these drugs that are necessary to maintain health in HIV-infected individuals also carry a significant burden of side effects. One of the recently recognized serious side effects is HIV protease inhibitor-induced insulin resistance leading to hyperglycemia which can progress to diabetes and ultimately to ketoacidosis which can also be life threatening (Carr, A., Samaras, K., Chrisholm, D.J., and Cooper, D.A.

(1998) Lancet 351 1881-1883; Carr, A., Samaras, K., Burton, S., Freund, I., Chisholm, D.J., Cooper D.A. (1998) AIDS 12, F51-F58).

In addition to insulin resistance, other related metabolic disorders such as lipodystrophy and hypertriglyceridemia are also observed in patients treated with HIV protease inhibitors (Roth, V.R., Kravcik, S., Angel, J.B. (1998) Clin Infect Dis 27,65 -67; Safrin, S., and Grunfeld, C, (1999) AIDS 13, 2493-2505; Carr, A., Samaras, K., Thorisdottir, A., Kaufmann, G.R., Chrisholm, D.J., and Cooper, D.A. (1999) Lancet 353, 2093-2099; Behrens, G., Dejam, A., Schmidt, H., Balks, H-J., Brabant, G., Komer, T., Stoll, M., and Schmidt, R.E. ( 1999) AIDS 13, F63-F70). This metabolic complex of secondary effects of these very important drugs has all the specific characteristics of the insulin resistance condition referred to as the X-syndrome (Reaven, G.M. (1993) Annu. Rev. Med. 44, 121-131).

For some patients, these secondary metabolic effects severely limit the use of these life-saving drugs. The side effect profile was not recognized early in the development of these drugs, but when these inhibitors entered general clinical use this side effect problem manifested itself in a substantial percentage of the treated population. The problem comes as a class effect as all currently available HIV protease inhibitor drugs exhibit this severe effect.

The molecular origin of this phenomenon has recently been identified in 3T3 LI adipocytes (Murata, H., Hruz, P.W., and Mueckler, M. (2000) The Journal of Biological Chemistry 275: 27, 20251-20254). The publication provides evidence that at least three of the commercially available HIV protease inhibitor drugs also prevent the glucose transporter from localizing the cell membrane with consequent inhibition of jucose uptake by these cells. This inhibition of cellular glucose transport to cells by the effect of these HIV protease inhibitors is in agreement with the increases in glucose and lipids observed in clinical controls for some patients treated with these protease inhibitor drugs.

Insulin receptor activators are known to stimulate the displacement of the glucose transporter to the cell membrane and thereby stimulate the subsequent intake of extracellular glucose. Various classes of compounds are known to act as insulin receptor activators. Insulin receptor activators comprise compounds of the structural classes of formulas I to VII indicated below. Examples of compounds of Formula I-II are described in WO 00/71506 and WO 01/12591. The synthesis of compounds of formula III and IV is described below in the "Examples" part. Examples of compounds of formula V and VI are reported in U.S. Pat. n. 6,051,597 and WO 99/51225, and examples of compounds of formula VII have been reported in U.S. Pat. n. 5,851,988 and 5,830,918. Furthermore, compounds such as azo dyes have been indicated by Geier et al. (U.S. Patent No.

6,020,374).

BRIEF SUMMARY OF THE INVENTION

The invention relates to the use of insulin receptor activating compounds for the treatment of diseases induced by the use of the HIV protease inhibitor. In particular, the present invention describes the use of insulin receptor activating compounds for the treatment of insulin resistance induced by the HIV protease inhibitor, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia in humans. These insulin receptor activating compounds may also be used together with insulin to treat diseases related to the use of HIV protease inhibitors, such as HIV protease inhibitor-induced insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia in humans.

The applicants found that compounds which sensitize the insulin receptor reverse the side effect of the HIV prosthesis inhibitor of metabolic disorders such as those mentioned above. The applicants found that compounds that are insulin receptor activators can reverse the inhibition of glucose intake caused by HIV protease inhibitor drugs. Thus, the applicants herein disclose that compounds which enhance glucose transport to HIV protease inhibitor treated cells can ensure improvement of the therapy-limiting side effect in protease inhibitor treated patients. Insulin receptor activating compounds, as described herein, may be an effective therapy for HIV protease inhibitor-induced insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia.

The present invention encompasses the use of any insulin receptor activating compound, except insulin, for the treatment of a disease related to the use of the HIV protease inhibitor such as insulin resistance, hyperglycemia, diabetes, ketoacidosis. , lipodystrophy and hypertriglyceridemia. The present invention further encompasses the use of any insulin receptor activating compound other than insulin, for the treatment of HIV protease inhibitor-induced insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy or hypertriglyceridemia in humans. . In particular, the compounds of formula I-VII are described herein as useful in the treatment of diseases related to the use of HIV protease inhibitors, and for the treatment of insulin resistance induced by an HIV protease inhibitor, of hyperglycemia. , diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia in humans. The methods according to the invention may also comprise the co-administration of insulin together with the administration of receptor activating compounds for the treatment of diseases related to the use of HIV protease inhibitors, and for the treatment of insulin resistance induced by HIV protease inhibitor, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia in humans. Compounds of formula I-IV are also described as being useful in the treatment of diabetes in copending U.S. applications. series n. 09 / 579.279, 60 / 208.591 and PCT / US00 / 14644.

According to one aspect, the present invention relates to pharmaceutical compositions comprising (i) a pharmaceutically acceptable carrier and (ii) as an active ingredient, a compound of formula I:

in which:

R <1> and R <2> are substituents on ring A and are, independently,

R <3> and R <4> are independently hydrogen or lower alkyl or R <3> and R <4> together are - (CH2) 2-, - (CH2) 3- O - (CH2) 4-,

R <5> and R <6> are independently hydrogen, lower alkyl, lower substituted alkyl, cyano, halogen, nitro,

each R <7> and R <8> is independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, lower arylalkyl, lower substituted arylalkyl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl or heteroaryl replaced,

each Y is a non-interfering substituent, each x is, independently, 0, 1 or 2, and the urea bond binds a carbon atom denoted by c with a carbon atom denoted by d,

or pharmaceutically acceptable salts thereof, optionally in the form of a single stereoisomer or mixtures of stereoisomers,

for the treatment of insulin resistance induced by the HIV protease inhibitor, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridaemia and ketoacidosis in humans.

In a first embodiment of this aspect of the invention the compounds of formula I, or their pharmaceutically acceptable salts, are used in pharmaceutical compositions without there being any Y bonded to a naphthalene ring through an azo bond, and if R <1> and R <2> are both -S020H, (i) no Y is -S020H; (ii) neither R <5> nor R <6> is -S020R <8> or -0S02R <8>; and (iii) R <5> and R <6> are not both selected from the group consisting of hydroxyl and hydrogen, unless at least one of (Y) x is (Y ') x', where x 'is 1 or 2 and Y 'is a halogen radical.

According to another aspect, the present invention relates to pharmaceutical compositions comprising (i) a pharmaceutically acceptable vehicle and (ii) as an active ingredient a compound of formula II for the treatment of insulin resistance induced by the HIV protease inhibitor, hyperglycemia , diabetes, lipodystrophy, hypertriglyceridemia and ketoacidosis in humans:

Formula II

in which:

R <1> and R <2> are independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, -C (0) R <4>, -C (0) 0R <4>, -C ( 0) NR <4> R <5>, -S (0) 2R <4>, -S (0) 20R <4>, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocycline, lower arylalkyl, lower substituted arylalkyl, lower heteroarylalkyl , lower substituted heteroarylalkyl or lower alkenyl, or R <1> and R <2>, together with the nitrogen to which they are bound, are C3-9 heteroaryl, C3-5 heterocyclyl or -N02,

R <3> is a substituent on the B ring, and is -S020R <6>, -C (0) OR <6>, -S02NR <6> 2, -C (0} NR <6> 2, or tetrazole ;

each ligand -WY- between the naphthyl and the phenyl intersects the ring A on the naphthyl and is, independently, (), (),

each R <4> and R <5> is independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, lower arylalkyl, lower substituted arylalkyl, substituted heteroaryl, heteroaryl, lower heteroarylalkyl, heteroaryl alkyl substituted, heterocyclyl, heterocyclyl substituted or lower alkenyl, each R <6> and R <7> is independently hydrogen or lower alkyl,

each R <8> is independently hydrogen, lower alkyl, substituted lower alkyl, lower arylalkyl, substituted lower arylalkyl, substituted heteroaryl, heteroaryl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, lower alkenyl, nitro, halo, cyano ,

each R <9> is independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, lower arylalkyl or substituted lower arylalkyl,

each Z is a non-interfering substituent,

each x and v is, independently, 0, 1, 2 or 3, and

R <10> is aryl, substituted aryl, heteroaryl or substituted heteroaryl, or pharmaceutically acceptable salts thereof, optionally in the form of a single stereoisomer or mixture of their stereoisomers.

According to another aspect, the present invention relates to pharmaceutical compositions comprising (i) a pharmaceutically acceptable vehicle and (ii) as an active ingredient a compound of formula III for the treatment of insulin resistance induced by an HIV protease inhibitor, hyperglycemia , diabetes, lipodystrophy, hypertriglyceridaemia and ketoacidosis in humans:

Formula III

in which:

R <1> and R <2> are independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, lower arylalkyl, lower substituted arylalkyl, lower heteroarylalkyl, lower substituted heteroarylalkyl or lower alkenyl, or R <1> and R <2>, together with the nitrogen atom to which they are connected, are C3-9 heteroaryl or C3-5 heterocyclyl.

Z is OH, halogen, OR <1> or NR <1> R <2>, where R <1> and R <2> have the previously indicated meaning, or their pharmaceutically acceptable salts, optionally in the form of a single stereoisomer or mixture of stereoisomers.

According to another aspect, the invention relates to pharmaceutical compositions comprising (i) a pharmaceutically acceptable vehicle and (ii) as an active ingredient a compound of formula IV, for the treatment of insulin resistance induced by an HIV protease inhibitor, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and ketoacidosis in humans:

Formula IV

in which:

R <1>, R <2> and R <4> are independently hydrogen, lower alkyl, lower substituted alkyl, halogen, hydroxyl, substituted alkyloxy, carboxyl,

R <2> is hydrogen, lower alkyl, substituted alkyl, halogen, hydroxyl, alkoxy, substituted alkoxyl, carboxyl, or -C (O) NR <11>,

R <5> is hydrogen, lower alkyl, lower substituted alkyl or aryl,

R <6> and R <7> are independently hydrogen or carboxyl,

R <8> and R <9> are independently hydrogen, lower alkyl, substituted lower alkyl, halogen, hydroxyl, alkoxy, carboxyl, -NR <11> R <12>, -C (0) NR <11> R <12>,

R <10> is lower alkyl, lower substituted alkyl, halogen, carboxyl, -C (0) NR <11> R <12>,

R <11> and R <12> are independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, lower arylalkyl, lower substituted arylalkyl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl or heteroaryl- C (0) -substituted aryl, or aryl,

or pharmaceutically acceptable salts thereof, optionally in the form of a single stereoisomer or mixture of their stereoisomers.

According to another aspect, the present invention relates to pharmaceutical compositions comprising (i) a pharmaceutically acceptable vehicle and (ii) as an active ingredient a compound of formula V for the treatment of insulin resistance induced by an HIV protease inhibitor, hyperglycemia , diabetes, lipodystrophy, hypertriglyceridemia and ketoacidosis in man:

Formula V

in which

the Y ring represents a 5 or 6 element condensed aryl or heteroaryl ring, which is optionally substituted by 1 to 4 groups selected from R <1>,

X represents 0, S (0) m or N, where m is 0, 1 or 2;

A represents an element chosen from the group consisting of:

(a) a mono- or bicyclic aryl group having 6 to 10 elements

(b) an isolated monocyclic heteroaryl group having 5 or 6 elements

(c) a bicyclic heteroaryl group having 9 to 10 elements, attachment to which occurs through a 6-element ring, or

(d) an 8-membered bicyclic heteroaryl group, the heteroaryl groups having from 1 to 4 heteroatoms selected from O, S (O) m and N, said aryl and heteroaryl groups being optionally replaced by 1 to 3 R <1> groups,

R <1> is chosen independently between:

halogen,

where m is 0, 1 or 2;

R <2> is chosen independently from:

or their pharmaceutically acceptable salts, optionally in the form of a single stereoisomer or mixture of their stereoisomers.

According to another aspect, the invention relates to pharmaceutical compositions comprising (i) a pharmaceutically acceptable vehicle and (ii) as an active ingredient a compound of formula VI for the treatment of insulin resistance induced by an HIV protease inhibitor, hyperglycemia , diabetes, lipodystrophy, hypertriglyceridaemia and ketoacidosis in humans:

Formula VI

in which

R <1> is hydrogen or methyl

R <2> is -CH2CH3 OR -CH = CH2

R <3> is -CH = CH-C (CH3) = CH2; CH2-CH = C (CH3) 2 or -CH2-CH2-CH = C (CH3) 2,

or pharmaceutically acceptable salts thereof, optionally in the form of a single stereoisomer or mixture of its stereoisomers.

According to another aspect, the present invention relates to pharmaceutical compositions comprising (i) a pharmaceutically acceptable vehicle and (ii) as an active ingredient a compound of formula VII for the treatment of insulin resistance induced by an HIV protease inhibitor, hyperglycemia , diabetes, lipodystrophy, hypertriglyceridaemia and ketoacidosis in humans:

Formula VII

m which

Q and Q 'are hydrogen or parts:

R <1> and R <2> are, independently,

or tetrazole

R <3> and R <4> are independently

O tetrazole R <5> and R <6> are independently hydrogen, lower alkyl, lower substituted alkyl, cyano, halogen, nitro,

each R <7> and R <8> is independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, lower arylalkyl, lower substituted arrylyl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl or heteroaryl replaced,

each Y is a non-interfering substituent, and each x is, independently, 0, 1 or 2, or pharmaceutically acceptable salts thereof, optionally in the form of a single stereoisomer or mixture of its stereoisomers.

DETAILED DESCRIPTION OF THE INVENTION

(a) Definitions:

"Alkyl", as in "alkyl" or "alkyloxy", means a monovalent C1-20 hydrocarbyl group which may be linear, branched or cyclic. "Lower alkyl", as in "lower alkyl", "lower haloalkyl", "lower arylalkyl", or "lower heteroarylalkyl", means an alkyl

The term "lower alkyl" includes such groups as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclopropylmethyl, cyclohexyl or cyclohexylmethyl. The lower C1-6 alkyls are preferred.

A substituted alkyl or lower substituted alkyl is an alkyl or lower alkyl, respectively, which is typically mono-, di- or trisubstituted with a group such as aryl, substituted aryl, heteroaryl, nitro, cyano, halogen,

wherein R and R 'are independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, heteroaryl, lower heteroarylalkyl, lower substituted arylalkyl or lower arylalkyl. Substituted alkyls or substituted lower alkyls which are substituted with 1 to 3 of the substituents selected from the group consisting of cyano, halogen, lower alkyloxy, thio, nitro, amino or hydroxyl are particularly preferred.

The term "lower haloalkyl" indicates a lower alkyl substituted with 1 to 3 halogen groups, and is exemplified by radicals such as -CF3, -CH2CF3 and -CH2CCI3.

"Aryl", as in "aryl", "aryloxy" and "lower arylalkyl", means a radical derived from an aromatic hydrocarbon containing 6 to 20 carbon atoms, having a single ring (e.g. phenyl) or two or more rings condensed, preferably 2 to 3 condensed rings (for example naphthyl), or 2 or more aromatic rings, preferably 2 to 3 aromatic rings, which are linked by a single bond (such as biphenyl). The aryl is preferably a C6-12aryl and even more preferably a C6-14aryl.

A "substituted aryl" is an aryl radical substituted, one or more times, with a group such as alkyl, substituted alkyl, halogen, cyano, nitro,

wherein R and R 'are independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, heteroaryl, lower heteroarylalkyl, lower arylalkyl or substituted lower arylalkyl. A substituted aryl can be substituted one or more times with any combination of the radicals indicated above. Preferably, however, the substituted aryl is mono-, di-, or trisubstituted. Particularly preferred substituents are substituted aryl, lower alkyl, lower haloalkyl, halogen, cyano, thio, nitro, amino, lower alkyloxy or hydroxyl. The radicals

wherein R and R 'are, independently, hydrogen or a lower alkyl, they are also particularly preferred substituents of substituted aryls on the compounds of the present invention.

"Heteroaryl", as in heteroaryl and lower heteroarylalkyl, means a radical derived from an aromatic hydrocarbon containing 5 to 14 ring atoms, 1 to 5 of which are heteroatoms independently selected from N, 0, or S, and include monocyclic, condensed heterocyclic, and condensed carbocyclic rings and heterocyclic aromatic rings (such as thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, isobenzofuranyl, purinyl, isoquinolyl, pteridinyl, imidazolyl, pyrolinyl, pyridinyl, etc. ).

A "substituted heteroaryl" can have 1 to 3 substituents such as alkyl, substituted alkyl, halogen, cyano, nitro,

wherein R and R 'are independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, heteroaryl, lower heteroarylalkyl, lower arylalkyl or substituted lower arylalkyl. Furthermore, every two adjacent substituents on the heteroaryl ring can optionally form a lower alkylenedioxy. Particularly preferred substituents on the substituted heteroaryl include hydroxyl, halogen, lower alkyloxy, cyano, thio, nitro, lower alkyl, lower haloalkyl or amino.

"Heterocyclyl" means a radical derived from a cyclic aliphatic hydrocarbon containing 5 to 14 ring atoms, 1 to 5 of which are independently selected heteroatoms from N, 0 or S. Monocyclic rings (such as tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, etc.).

A "substituted heterocyclyl" can have from 1 to 3 substituents, preferably substituents such as alkyl, substituted alkyl, halo, cyano, nitro, -OR,

wherein R and R 'are independently hydrogen, lower alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, lower heteroarylalkyl, lower arylalkyl or substituted lower arylalkyl. Preferred substituents on a substituted heterocyclyl include lower alkyl, lower haloalkyl, halogen, cyano, thio, amino, lower alkyloxy or hydroxyl.

"Lower arylalkyl" means a lower alkyl radical which is substituted with an aryl, as defined above. A "substituted lower arylalkyl" means a lower arylalkyl radical having 1 to 3 substituents on the aryl part or the alkyl part of the radical, or both.

"Lower heteroarylalkyl" means a lower alkyl radical substituted with a heteroaryl, as defined above. A "substituted heteroarylalkyl" means a lower heteroarylalkyl radical having 1 to 3 substituents on the heteroaryl part or the alkyl part of the radical, or both.

A "lower alkyloxyl" indicates an -OR radical, wherein R is a lower alkyl.

"Lower alkenyl" means any unsaturated C2-10 branched or unbranched group having the specified number of carbon atoms, or up to 10 carbon atoms if there is no limitation on the number of carbon atoms; and having one or more double bonds in the group. Lower alkenyl is exemplified by ethenyl, propenyl, butenyl, pentenyl and hexenyl, in their various isomeric forms, in which unsaturated bonds can be placed anywhere in the group.

"Halogen" means bromine, iodine, fluorine or chlorine. A "non-interfering substituent" means a substituent which, when present on a given compound, does not substantially decrease or otherwise inhibit a particular desired bioactivity of the compound, such as the ability of the compound to reverse the inhibition of glucose uptake caused by HIV protease inhibitor drugs, to activate the insulin receptor or to stimulate the uptake of glucose into the cells. The presence of the non-interfering substituent must not adversely affect the bioactivity of the compound by more than about 30%. Preferably, the non-interfering substituent decreases the bioactivity of the compound by less than about 10%. More preferably, the non-interfering substituent does not decrease the bioactivity of the compound in any detectable way. However, the effect of the presence of the non-interfering substituent on the compound need not be neutral. For example, the non-interfering substituent can optionally enhance a particular bioactivity of the compound. Suitable non-interfering substituents include, but are not limited to, hydrogen, alkyl, substituted alkyl, cyano, halogen, nitro, -SR, -OR, and -NRR ', wherein R and R' are, independently, hydrogen, lower alkyl or substituted lower alkyl.

A "pharmaceutically acceptable salt" can be any salt derived from an inorganic or organic acid or from an inorganic or organic base. The term "pharmaceutically acceptable anion" refers to the anion of such acid addition salts. The term "pharmaceutically acceptable cation" refers to a cation formed by the addition of a base. The salt and / or the anion or cation are selected so as not to be biologically or otherwise undesirable.

"Stereoisomers" are compounds that have the same sequence of covalent bonds and differ in the relative arrangement of their atoms in space.

"Internal salts" or "zwitterions" can be formed by transferring a proton from the carboxyl group to the isolated electron pair of the nitrogen atom in the amino group.

"Therapeutically effective amount" means the amount which, administered to an animal to treat a disease, is sufficient to carry out such treatment for the disease.

"Treating" or "treating" a disease in a mammal includes:

(1) prevent disease from occurring in a mammal that may be predisposed to disease but has not yet exhibited disease symptoms,

(2) inhibiting the disease, i.e. stopping or slowing its development,

(3) to alleviate the disease, that is, to bring about the regression of the disease, or

(4) relieve the symptoms of the disease, that is, decrease the effects of the disease.

"Disease" includes any unhealthy condition of a man, including, in particular, insulin resistance induced by the HIV protease inhibitor, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia.

(b) Compounds of the invention

According to one aspect, the present invention relates to pharmaceutical compositions comprising (i) a pharmaceutically acceptable vehicle and (ii) as an active ingredient an insulin receptor activator, for the treatment of insulin resistance induced by the HIV protease inhibitor , hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and ketoacidosis in humans. Such pharmaceutical compositions can comprise any insulin receptor activating compound, including compounds of formula I to VII described herein.

Compounds useful in carrying out the invention can be prepared by processes known to those skilled in chemistry. Furthermore, examples and syntheses of compounds of formula I-II are described in WO 00/71506 and WO 01/12591. The syntheses of the compounds of formula III and IV are generally described below. The compounds of formulas V and VI (and their syntheses) are described in U.S. Pat. n.

6,051,597 and WO 99/51225. The compounds of formula VII (and their synthesis) are described in U.S. Pat. n. 5,851,988 and 5,830,918.

Certain compounds of the invention may contain one or more chiral centers. In these cases, all stereoisomers are also within the scope of the present invention. Compounds of the invention comprise the single isolated stereoisomers as well as mixtures of such stereoisomers.

The compounds of the invention further comprise pharmaceutically acceptable salts of the compounds described. These pharmaceutically acceptable salts are suitable for use in all pharmaceutical methods and compositions of the present invention.

Pharmaceutically acceptable salts include salts which can be prepared when the acidic protons present are capable of reacting with inorganic or organic bases. Typically, the parent compound is treated with an excess of an alkaline reactant, such as hydroxide, carbonate or alkoxide, containing a suitable cation. Cations such as Na <+>, K <+>, Ca <2+> and NH4 <+> are examples of cations present in pharmaceutically acceptable salts. Sodium salts are especially useful. Acceptable inorganic bases therefore include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. The salts can also be prepared using organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, ethanolamine and trometamine.

If a compound of the invention contains a basic group, an acid addition salt can be prepared. Acid addition salts of the compounds are prepared in a standard way in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid (obtaining the sulfate and bisulfate salts), nitric acid, phosphoric acid and similar, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, mayionic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid , methanesulfonic acid, ethanesulfonic acid, salicylic acid, ptoluenesulfonic acid, hexanoic acid, heptanoic acid, cyclopentanpropionic acid, lactic acid, o- (4-hydroxybenzoyl) benzoic acid, 1,2-ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo [2.2.2.] oct-2-ene-1-carboxylic acid, glucoheptonic acid, gluconic acid, aci do 4,4'-methylenbis (3-hydroxy-2-naphthoic), 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid, glucuronic acid, glutamic acid, 3-hydroxy-2-naphthoic acid, stearic acid , muconic acid and the like.

Some of the compounds of the invention can form internal salts or zwitterions.

Pharmaceutical compositions of all compounds of the present invention are contemplated. These pharmaceutical compositions comprise (i) an insulin receptor activator as an active ingredient and (ii) a pharmaceutically acceptable carrier. Furthermore, these pharmaceutical compositions comprise (i) a compound of the invention as an active ingredient and (ii) a pharmaceutically acceptable carrier.

Pharmaceutical compositions of the compounds of the present invention, or derivatives thereof, can be formulated as lyophilized solutions or powders for parenteral administration. The powders can be reconstituted by adding a suitable diluent or other pharmaceutically acceptable carrier before use. The liquid formulation is generally a buffered isotonic aqueous solution. Examples of suitable diluents are normal isotonic saline solutions, 5% dextrose solution in water, or solution buffered with sodium or ammonium acetate. Such formulations are especially suitable for parenteral administration, but can also be used for oral administration. It may be desirable to add excipients such as polyvinylpyrrolidinone, gelatin, hydroxycellulose, gum arabic, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively these compounds can be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to improve or stabilize the composition or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols, and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, gum arabic, agar or gelatin. The carrier may also comprise a delayed release product such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier can vary and is preferably comprised between about 20 mg and about 1 g per dosage unit. The pharmaceutical preparations are prepared according to conventional pharmacy techniques which provide for grinding, mixing, granulation and compression, when necessary, to obtain tablets; or grinding, mixing and introduction into hard gelatin capsules. When using a liquid carrier, the preparation is preferably in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. This liquid formulation can be administered directly by mouth or placed in a hard gelatin capsule.

(c) Processes of use of the compounds of the present invention.

The insulin receptor activating compounds of the present invention have been shown to stimulate insulin receptor autophosphorylation. Furthermore, these compounds have been shown to improve glucose transport in cultured fibroblast cells after treatment of the cells with various HIV protease inhibitors. Although the applicants do not wish to bind to any theory, it is believed that the HIV protease inhibitors reduce the binding of glucose transporters with the cell membrane and that the compounds of the invention are effective in improving glucose transport into inhibitor-affected cells. of HIV protease by enhancing the membrane binding activity and other activities of glucose transporters.

The ability of the compounds of the present invention to stimulate glucose uptake into cells indicates their utility in the treatment and management of patients who have HIV protease inhibitor-induced insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy or hypertriglyceridemia. Due to the activity of the compounds of the invention, they can be used to stimulate the kinase activity of an insulin receptor, to improve the activation of the insulin receptor by insulin, to improve the insulin stimulation of cellular glucose intake and to stimulate glucose intake in individuals who have HIV protease therapy-induced diabetes, ketoacidosis, insulin resistance, hyperglycemia, lipodystrophy or hypertriglyceridaemia. Hence, the insulin receptor activating compounds and, more specifically, the compounds of the invention, can be used in the preparation of medicaments for the treatment of any of the diseases induced by the use of an HIV protease inhibitor.

The method may also include treating a patient who has complications from HIV protease therapy with one or more additional forms of therapy for insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy, or hypertriglyceridaemia, such as insulin administration. to the patient. Insulin or other form of treatment can be administered to the patient in a therapeutically effective amount when used in conjunction with a compound of the invention. This therapeutically effective amount of insulin or other form of treatment, when used in combination with a compound of the invention may be less than the amount of insulin that would be therapeutically effective if administered to the patient alone. It will be understood that the insulin which is administered in any of the treatments of the present invention may be isolated from a natural source or be recombinant insulin. Furthermore, insulin can be replaced with an analogue thereof in any of the treatments of the present invention. Thus, a medicament prepared (for the treatment of any of the diseases induced by the use of an HIV protease inhibitor) using an insulin receptor activating compound, more specifically a compound of the invention, may also comprise a further form treatment, such as treatment with insulin or an insulin analogue, of any disease induced by the use of the HIV protease inhibitor.

Methods of the invention for the treatment of HIV protease-induced diabetes, ketoacidosis, lipodystrophy, hypertriglyceridaemia, insulin resistance or hyperglycemia by combination therapy may also include administering the compound of the invention to the patient in combination with an antidiabetic agent. non-insulin, or other treatment for type II diabetes. For example, the antidiabetic drug that is administered to the mammal in combination with a compound of the invention may optionally be a thiazolidinedione, such as troglitazone, or a sulphonylurea. The total amount of drug combination (compound of the invention plus insulin and / or other antidiabetic drugs) administered to the mammal for the treatment of type II diabetes must be a therapeutically effective amount, although the amount of each of the individual drugs used in therapy combined may be suboptimal for therapeutic purposes if this drug were administered alone to a mammal with type II diabetes. Thus, a medicament prepared (for the treatment of any of the diseases induced by the use of the protected HIV inhibitor) using an insulin receptor activating compound, more specifically a compound of the invention, may also comprise a further form of treatment, such as, for example, a non-insulin antidiabetic agent, of any disease induced by the use of the protected HIV inhibitor.

The methods of the invention for the treatment of HIV protease-induced diabetes, ketoacidosis, lipodystrophy, hypertriglyceridemia, insulin resistance or hyperglycemia by combination therapy may also include administering one compound of the invention to the patient together with another compound of the invention. Thus, a medicament prepared (for the treatment of any of the diseases induced by the use of an HIV protease inhibitor) using an insulin receptor activating compound, more specifically a compound of the invention, may also comprise another compound of the invention.

The compounds of the present invention can be used in the preparation of a medicament for the treatment of a disease induced by the use of an HIV protease inhibitor.

The compounds of the present invention are thus used to improve glucose uptake in patients subjected to HIV protease therapy, who need such treatment. The treatment method comprises administering an effective amount of the selected compound of the invention, preferably dispersed in a pharmaceutical carrier. Preferred routes of administration are the parenteral and oral routes.

The compounds of the invention can be administered by any route suitable for the subject to be treated and the nature of the subject's disease. Routes of administration include, but are not limited to, administration by injection, including intravenous, intraperitoneal, intramuscular and subcutaneous injection, transmucosal or transdermal administration, by topical application, nasal spray, suppositories and the like or may be administered orally. The formulations may optionally be liposomal formulations, emulsions, formulations intended for administering the drug through mucosal membranes or transdermal formulations. Suitable formulations for each of these delivery methods can be found, for example, in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, PA.

The dosage units of the active ingredient are generally selected in the range from 0.01 to 1000 mg / kg, preferably from 0.01 to 100 mg / kg and more preferably from 0.1 to 50 mg / kg, but will be quickly determined. by an expert in the art depending on the route of administration, age and disease of the patient. The compounds of the invention are more preferably administered in dosage units of 1 to 10 mg / kg. These dosage units can be administered 1 to 10 times a day for acute or chronic disease.

(d) Examples

The following examples serve to illustrate the present invention and are not intended to limit the scope of the invention, but are intended to teach how to make and use the compounds of the present invention.

The compounds of the present invention are prepared by conventional organic chemistry processes. In some cases, protective groups can be introduced which are removed at the end. Protective groups suitable for amino, hydroxyl, carboxylic groups are described in Greene, et al., Protective Groups in Organic Synthesis, Second Ed., John Wiley and Sons, New York, 1991. Activation of carboxylic acids can be achieved using various different reagents, as described in Larock, Comprehensive Organic Transformation, VCH Publishers, New York, 1989.

The compounds of formula III are prepared with conventional methods of organic chemistry. Generally, a compound of formula

<1 2>

in which:

R <1> and R <2> are independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, lower arylalkyl, lower substituted arylalkyl, lower heteroarylalkyl, lower substituted heteroarylalkyl or lower alkenyl, or R <1> and R <2>, together with the nitrogen atom to which only attached, can form C3-9 heteroaryl or C3-5 heterocyclyl, and

Z is OH, C1, Br, F, OR <1>, or NR <1>, where R <1> and R <2> have the previously indicated meaning, or a pharmaceutically acceptable salt thereof, or a single stereoisomer thereof or a mixture of its stereoisomers;

can be prepared with a process that includes:

(a) reaction of a 1,3,5-benzentricarbonyl trihalide in which the halogen is selected from the group consisting of chlorine, bromine and fluorine, with at least 1 to at least 3 moles of HNR <1> R <2>, in where R <1> and R <2> have the previously indicated meaning;

(b) reaction of an activated carboxyamide of formula

with a primary amine R <3> NH2 or a secondary amine R <3> R <4> NH, wherein M is any substituent that allows the reaction with said amine; for example M may be halogen, formate, imidazole or some other promoting or coupling reagent; or

(c) acid esterification of a compound of formula

CONR <1> R <2>

MOC

to form a compound of formula A; or

(d) chemical processing of one or more substituents of the substitutes R <1> or R <2>, wherein said substituent is convertible into another substituent; or

(e) conversion of a compound of formula A with three NRR <2> groups to a compound of formula I with one or two NRR <2> groups, or

(f) conversion of the compound of formula A to a pharmaceutically acceptable salt; or

(g) conversion of a salt of the compound of formula A to a free compound; or

(h) converting a salt of the compound of formula A to a pharmaceutically acceptable salt; or

(i) resolving a racemic mixture of any proportion of the compound of formula A to obtain a stereoisomer thereof.

Asymmetric compounds of formula III can be prepared through the following reaction scheme:

A benzyl ester of the compound of the invention is hydrolyzed (under basic hydrolysis conditions or by catalytic hydrogenolysis) to obtain a carboxylic acid of the compound; this carboxylic acid compound is subsequently transformed into an acid chloride of the compound which is reacted with an amine to obtain an asymmetrical form of the compound of the invention.

As previously shown, a variously protected monomethyl, or monobenzyl ester of benzene tricarboxylic acid can be converted to acid chloride using oxalyl chloride to obtain the corresponding mono-acyl chloride. The reaction with an amine allows to obtain the monoamide. Selective saponification of the methyl ester under alkaline conditions, followed by acid treatment, will form another carboxylic acid which can be converted to acid chloride using oxalyl chloride. The reaction with a second amine will form an asymmetric compound. The final carboxylic ester can be converted into the carboxylic acid with a greater forcing of the saponification conditions, or by catalytic hydrogenolysis. After isolation of the carboxylic acid, the carboxylic acid can be converted to the acid chloride and then reacted with a third amine to obtain a benzene compound with three different amide substituents. It will be evident to those of ordinary skill in the art that diamines can be used instead of monoamines in the above synthesis.

In some cases, protective groups can be introduced which are subsequently removed.

Protective groups suitable for the animino, hydroxyl, carboxyl groups are described in Green, et al., Protective Groups in Organic Synthesis, Second Ed., John Wiley and Sons, New York, 1991. Activation of carboxylic acids can be achieved using various different reagents, as described in Larock, Comprehensive Organic Trans formations, VCH Publishers, New York, 1989.

The compounds of formula IV are prepared with conventional methods of organic chemistry.

Generally the preparation process includes:

(a) reaction of a bisamide iodo of formula

wherein R <1> -R <7> have the previously indicated meaning, with a substituted styrene or styrene of formula

in which R <8> -R <10> have the meaning previously indicated; or

(b) chemical processing of one or more substituents R <1> -R <10> in which said substituent is convertible into another substituent R <1> -R <10>; or

(c) introduction of a substituent R <1> -R <10> in 1, 2 or all 3 phenyl rings; or

(d) deprotection of a protected group; or (e) salt formation or interconversion; or

(f) hydrolysis of the ester; or

(g) release of a free acid or base of a compound of formula IV, wherein R <1> -R <12> have the previously indicated meaning; or

(h) separation or synthesis of stereoisomers. The reaction of bisamide iodo with styrene or substituted styrene, shown in (a) above, can be carried out between 40 ° C and 120 ° C in the presence of solvents such as DMF, toluene, methylene chloride or the like.

Chemical processing of one or more R <1> -R <10> substituents through the conversion of one such substituent to another substituent can be accomplished by hydrolysis, salt formation, acidification, alkylation, esterification, oxidation or reduction.

In hydrolysis, an ester or amide compound is dissociated by reaction with water. The hydrolysis is catalyzed by acid or base, and the hydrolysis of an amide generally requires more energetic conditions (e.g. a higher concentration of sulfuric acid from 1 to 100 ° C for a time of 1 to 5 hours) than necessary for the hydrolysis of esters. The hydrolysis reactions can also be carried out with aqueous hydrochloric acid between 100 and 150 ° C and can take up to 18 hours.

In the formation of the salt, a free acid is converted into a salt by adding a basic reagent, such as aqueous solution of sodium hydroxide or triethanolamine, which replaces all or part of the hydrogen ions of the acid with one or more cations of a base . Conversion of a compound to its corresponding acid addition salt is accomplished by treatment with a stoichiometric amount of a suitable acid, such as hydrochloric acid. Typically, the free base is dissolved in a polar organic solvent, such as methanol or ethanol, and the acid is added in methanol or ethanol. The temperature is maintained between 0 and 50 ° C. The corresponding salt precipitates spontaneously or can be extracted from the solution with a less polar solvent. In acidification, a chemical compound is transformed into an acid.

In alkylation, an alkyl group is added to or substituted for another group in a compound. The alkylation is carried out in a suitable solvent such as acetonitrile, DMF or THF, between 0 ° C and 160 ° C, typically between about 25 ° C and reflux, and takes about 1 to 18 hours.

The esterification reaction leads to the formation of at least one ester. Briefly, the compound is reacted with 1.0 to 5.0, preferably 2.0, molar equivalents of an alkanol, a thiol or ammonia, a monoalkyl, or dialkylamine, or a heterocyclic aminoalkanol, optionally in the presence of a amounts from 1.0 to 1.5, preferably 1.25 molar equivalents of a tertiary organic base such as 4-dimethylaminopyridine or, preferably, triethylamine, in an organic solvent such as dioxane, tetrahydrofuran or, preferably, dichloromethane. The reaction occurs between -10 and 50 ° C, preferably at room temperature, for a time from 1 to 24 hours, preferably 4 hours.

Examples of synthesis of specific compounds usable in the invention are the following. Example 1

Compound 1

Preparation of the Compound 1

Disodium salt of 4-hydroxy-7- {[(5-hydroxy-7-sulfo (2-naphthyl)) amino] carbonylamino} naphthalene-2-sulfonic acid.

To 10.77 g (0.045 moles) of 7-amino-4-hydroxynaphthalene-2-sulfonic acid dissolved in 45 ml of 1N aqueous sodium hydroxide solution and 50 ml of water, 3.70 g (0.045 moles) are added of sodium acetate. The pH of the solution is above 9. The reaction is cooled below 5 ° C in an ice and water bath. 2.23 g (0.045 moles) of triphosgene dissolved in 15 ml of THF are then added in 3 portions. The pH of the reaction drops to 4-5 and is brought back to 7-8 with the dropwise addition of 1N aqueous sodium hydroxide solution. The TLC (ethyl acetate: isopropanol: water 6: 2: 1) indicates that the reaction is incomplete. Another 2.20 g (0.045 mol) of triphosgene in 10 ml of THF are added in successive portions, maintaining the pH above 7 by adding 1N aqueous sodium hydroxide solution. When it is judged that the reaction is complete, by TLC, the pH is brought to 1 with aqueous hydrochloric acid and the volatile products are removed by rotary evaporation. The solid product is collected by vacuum filtration. In this way 10.85 g of the desired compound are obtained.

7 - {[(7- (chlorosulfonyl) -5-hydroxy (2-naphthyl)) amino] carbonylamino} -4-hydroxynaphthalen-2-sulfonyl chloride.

500 mg (0.912 mmol) of disodium salt of 4-hydroxy-7 - {[(5-hydroxy-7-sulfo (2-naphthyl)) amino] carbonylamino} naphthalene-2-sulfonic suspended in 8 ml of oxychloride of phosphorus are added 25 ml of sulfolane: acetonitrile 1: 1 (volume / volume) and 0.5 ml of dimethylacetamide. The reaction mixture is left under stirring at room temperature for 16 hours. The reaction becomes a clear solution which is poured onto 500ml of ice. The ice mixture is placed in an ice bath and allowed to gradually warm up to room temperature. The resulting solid is collected by filtration under vacuum and washed with water. The solid is dried under high vacuum for 24 hours. 412 mg of the desired compound are obtained.

5 - {[(7- {[N- (7 - {[(4-chloro-3-benzenesulfonic acid) amino] olfonìl} -5-hydroxy (2-naphthyl) carbamoyl] amino} -4-hydroxy (2 -naphthyl)) sulfonyl] alunino} -2-chlorobenzensol phonic.

To 0.15 g (0.277 mmol) of 7 - {[(7- (chlorosulfonyl) -5-hydroxy (2-naphthyl)) amino] carbonylamino} -4-hydroxynaphthalene-2-sulfonyl chloride are added 1.5 ml of freshly distilled THF and then 0.105 g (0.610 mmoles) of 5-amino-2-chlorobenzenesulfonic acid. To this solution are added 67 μΐ (0.831 mmoles) of pyridine. The reaction is left under stirring at room temperature for 16 hours. The reaction is then separated between 1N hydrochloric acid (aqueous) and ethyl acetate. The aqueous layer is extracted a second time with ethyl acetate and the combined organic layers are dried over magnesium sulphate, filtered, then the volatile products are removed by rotating evaporation. 0.14 g of the desired compound are obtained.

Compound 2

Example 2

Reversal of the blockade of glucose transport to cells by the HIV protease inhibitor Stimulation of the insulin receptor leads to the transport of glucose from the blood to the cells, thereby modulating blood glucose levels. 3T3 LI fibroblasts (ATCC) are cultured in Dulbecco's modified Eagle medium (DMEM) with 10% fetal bovine serum (FBS). Cells are plated with a density of 3 x 10 <4> cells / mL in 96-well plates (0.1 mL / well). Two days after confluence, cells are treated for 3 days with 0.5 mM isobutylmethylxanthine (IBMX), 1 μΜ dexamethasone and 1.7 μΜ insulin. The cells are then transferred to DMEM

with 10% fetal bovine serum, supplemented with 1.7 μΜ insulin for a further 2 days. The cells are kept in DMEM with 10% FBS for another 4 days. Finally the cells are deprived of serum overnight in 0.1% bovine serum albumin (BSA) in DMEM.

The following day the cells are pretreated with Indinavir, Ritonavir or Amprenavir (the concentrations indicated in the following tables) in a buffer containing 150 mM NaCl, 1.7 mM KC1, 0.9 mM CaCl2, K2HP04 1.47 mM (pH 7, 4) and 0.01% of BSA x 6 minutes, then treated with a compound described in the present patent (56 μΜ of compound 1; 20 μΜ of compound 2) with or without 100 mM of insulin for 30 minutes. After incubation the cells are labeled with 2-deoxy-D-glucose labeled with <14> C (0.5 μCi / ml) and the incubation is continued for another 30 minutes at 37 ° C. The cells are then washed three times with ice-cold 20 mM PBS / glucose and used in 100 μl of lysis buffer (Hepes 50 mM, pH 7.6, 1% Triton X-100) for 30 minutes at room temperature. Radioactivity in the US is quantified by scintillation counting.

When <14> C-2-deoxy-D-glucose is transported into the cells, it is not released.

The transport of glucose is therefore proportional to the amount of radioactivity in the lysate.

Results:

Compounds 1 and 2 are shown to increase glucose transport activity in 3T3 L1 adipocytes which was previously inhibited by the presence of the HIV protease inhibitors Ritonavir, Indinavir or Amprenavir. Each of these drugs is known to induce insulin resistance and other related disorders in metabolism, such as lipodystrophy and hypertriglyceridaemia in patients treated with these HIV protease inhibitors.

The results are reported in the following tables:

Indinavir

Amprenavir

Ritonavir

Example 3

Compound 3

Preparation of the Compound 3

Compound 3 is synthesized by a method similar to that described in Example 1, except that in the final steps after the synthesis of 7 - {[(7- (chlorosulfonyl) -5-hydroxy (2-naphthyl)) amino] carbonylamino} -4-hydroxynaphthalen-2-sulfonyl chloride are the following:

5- {[(7 - {[N- (7- {[(3-carboxy-4-chlorophenyl) amino] sulfonyl} -5-hydroxy (2-naphthyl)) carbamoyl] amino} -4-hydroxy (2 -naphthyl)) sulfonyl] amino} -2-chlorobenzoic.

To 0.15 g (0.277 mmol) of 7 - {[(7- (chlorosulfonyl) -5-hydroxy (2-naphthyl)) amino] carbonylamino} -4-hydroxynaphthalene-2-sulfonyl chloride are added 1.5 ml of freshly distilled THF followed by 0.105 g (0.610 mmol) of 5-amino-2-chlorobenzoic acid. To this solution are added 67 μl (0.831 mmoles) of pyridine. The reaction is left under stirring at room temperature for 16 hours. The reaction is then partitioned between 1N hydrochloric acid (aqueous) and ethyl acetate. The aqueous layer is extracted a second time with ethyl acetate and the combined organic layers are dried over magnesium sulphate, filtered, then the volatile substances are removed by rotating evaporation. In this way 0.14 g of the desired compound are obtained.

Example 4

Protease inhibitor-mediated reversal of insulin resistance in normal rats by Compound 1

Male 9-week-old CD rats (Charles River Laboratories, Hollister CA) are used to study the effects of the protease inhibitor and Compound 1. Animals are kept on a 12-hour / 12-hour light / dark cycle and they are fasted for the night.

An aqueous solution of Indinavir sulfate is prepared and Compound 1 is prepared in PBS. Seven animals (average weight 300 g) are employed for each treatment condition. Animals are treated with either the vehicle or Indinavir sulfate or Indinavir sulfate and Compound 1 by oral administration. After 30 minutes, the animals are given glucose (2 g / kg) orally, then blood glucose is determined at 0, 10, 20, 30, 60, 90 and 120 minutes, taking blood from the tail. Glucose determinations are performed with a glucometer and with glucose papers (Bayer). The data obtained are shown in Figures 1 and 2.

Figure 1 shows the effect of Indinavir on blood glucose levels following oral glucose administration. Blood glucose levels are shown as a percentage of the "time 0" values.

Figure 2 shows the effect of Indinavir and Indinavir plus the compound on plasma insulin levels. Blood samples taken at minute 0 and minute 30 are analyzed to evaluate plasma insulin levels by ELISA (ALPCO Diagnostics, Windham, NH).

Claims (24)

CLAIMS 1. Use of an insulin receptor activating compound or a pharmaceutically acceptable salt thereof, wherein said compound is not insulin, in the preparation of a medicinal product for the treatment of a disease induced by the use of an HIV-protected inhibitor . Use according to claim 1, wherein the disease induced by the use of the protected HIV inhibitor is selected from the group consisting of insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia. 3. Use according to any one of claims 1 or 2, wherein the insulin receptor activating compound is a compound of formula Formula 1 in which: R <1> and R <2> are substituents on ring A and are, independent, -S02NR <7> 2, -C (0) NR <7> 2, -NR <7> S02R <7>, -NR <7> C (0) R <7>, -S020R <7>, -C (0) 0R <7>, -0S02R <7>, or -0C (0) R <7>, R <3> and R <4> are independently hydrogen or lower alkyl, or R <3> and R <4> together are - (CH2) 2- R <5> and R <6> are independently hydrogen, lower alkyl, lower substituted alkyl, cyano, halogen, nitro, each R <7> and R <8> is independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, lower arylalkyl, lower substituted arylalkyl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl or heteroaryl replaced, each Y is a non-interfering substituent, each x is, independently, 0,1 or 2, and the urea ligand connects a carbon atom denoted by c with a carbon atom denoted by d, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of its stereoisomers. The use according to claim 3, wherein no Y is bonded to a naphthalene ring through an azo bond in the compound. Use according to any one of claims 3 or 4 wherein, when R <1> and R <2> are both -S020H, (i) no Y is -S020H; (ii) neither R <5> nor R <6> are -S020R <8> or -0S02R <8>; and (iii) when no (Y) x is (Y ') x-, where x' is 1 or 2 and Y 'is a halogen radical, R <5> and R <6> are not both chosen from the group consisting from hydroxyl and hydrogen. Use according to claim 1 or claim 2, wherein the insulin receptor activating compound is a compound of formula Formula II in which: R <1> and R <2> are independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, -C (0) R <4>, -C (0) 0R <4>, -C (0) NR <4> R <5>, -S (0) 2R <4>, -S (0) 2OR <4>, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, lower arrisichyl, lower substituted arylalkyl, lower heteroarylalkyl, heteroarylalkyl lower substituted or lower alkenyl, or R <1> and R <2>, together with the nitrogen to which they are joined, are C3-9 heteroaryl, C3-5 heterocyclyl or -N02, R <3> is a substituent on the B ring and is -S02OR <6>, -C (0) 0R <6>, -S02NR <6> 2, -C (0) NR <6> 2 or tetrazole; each ligand -WY- between the naphthyl and the phenyl intersects the ring A on the naphthyl and is, independently, each R <4> and R <5> is independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, lower arylalkyl, lower substituted arylalkyl, substituted heteroaryl, heteroaryl, lower heteroarylalkyl, heteroaryl alkyl substituted, heterocyclyl, heterocyclyl substituted or lower alkenyl, each R <6> and R <7> is independently hydrogen or lower alkyl, each R <8> is independently hydrogen, lower alkyl, substituted lower alkyl, lower arylalkyl, substituted lower arylalkyl, substituted heteroaryl, heteroaryl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, lower alkenyl, nitro, halogen, cyano , -OR <9>, each R <9> is independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, lower arylalkyl or substituted lower arylalkyl, each Z is a non-interfering substituent, each x and v is, independently, 0, 1, 2 or 3, e R <10> is aryl, substituted aryl, heteroaryl or heteroaryl substituted, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of its stereoisomers. One according to any one of claims 1 or 2, wherein the insulin receptor activating compound is a compound of formula Formula III in which: R <1> and R <2> are independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, lower arylalkyl, lower substituted arylalkyl, lower heteroarylalkyl, lower substituted heteroarylalkyl or alkenyl lower, or R <1> and R <2>, together with the nitrogen atom to which they are joined, are C3-9 heteroaryl or C3-5 heterocyclyl, Z is OH, halogen, OR <1> or NR <1> R <2>, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of its stereoisomers. Use according to any one of claims 1 or 2, wherein the insulin receptor activating compound is a compound of formula Formula IV in which R <1>, R <3> and R <4> are independently hydrogen, lower alkyl, substituted lower alkyl, halogen, hydroxyl, substituted alkyloxy, carboxyl, -NR <11> R <12>, or -C ( 0) NR <11> R <12>, R <2> is hydrogen, lower alkyl, substituted alkyl, halogen, hydroxyl, alkoxy, substituted alkyloxy, carboxyl, -NR <11> R <12>, -NR <11> C (0) R <12>, O - C (O) NR <11>, R <5> is hydrogen, lower alkyl, lower substituted alkyl or aryl, R <6> and R <7> are independently hydrogen or carboxyl, R <8> and R <9> are independently hydrogen, lower alkyl, substituted lower alkyl, halogen, hydroxyl, alkoxy, carboxyl, -NR <11> R <12>, -C (0) NR <11> R <12>, R <10> is lower alkyl, lower substituted alkyl, halogen, carboxyl, -C (O) NR <11> R <12> R <11> and R <12> are independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, lower arylalkyl, lower substituted arylalkyl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl or heteroaryl- C (0) -aryl, or aryl, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of its stereoisomers. Use according to any one of claims 1 or 2, wherein the insulin receptor activating compound is a compound of formula Formula V in which ring Y represents a condensed 5- or 6-membered aryl or heteroaryl ring, which is optionally substituted with 1-4 groups selected from R <1> X represents O, S (0) m or N, where m is 0, 1 or 2; A represents an element chosen from the group consisting of: (a) a mono- or bicyclic aryl group having 6 to 10 elements (b) an isolated monocyclic heteroaryl group having 5 or 6 elements (c) a bicyclic heteroaryl group having 9 to 10 elements, attachment to which occurs through a 6-element ring, or (d) an 8-membered bicyclic heteroaryl group, the heteroaryl groups having from 1 to 4 heteroatoms selected from 0, S (0) m and N, said aryl and heteroaryl groups being optionally substituted with 1 to 3 R <1> groups; R <1> is independently chosen between: where m is 0, 1 or 2; R <2> is chosen independently from: H, OH, halogen, -C2-4alkenyl, heterocyclyl where m is 0, 1 or 2, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of its stereoisomers. Use according to any one of claims 1 or 2, wherein the insulin receptor activating compound is a compound of formula Formula VI R <1> is hydrogen or methyl R <2> is -CH2CH3 OR -CH = CH2 or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of its stereoisomers. Use according to any one of claims 1 or 2, wherein the insulin receptor activating compound is a compound of formula Formula VII in which Q and Q 'are hydrogen or a part: R <1> and R <2> are, independently, or tetrazole R <3> and R <4> are, independently, or tetrazole R <5> and R <6> are independently hydrogen, lower alkyl, lower substituted alkyl, cyano, halogen, nitro, each R <7> and R <8> is independently hydrogen, lower alkyl, lower substituted alkyl, aryl, substituted aryl, lower arylalkyl, lower substituted arrylyl, lower heteroarylalkyl, lower substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl or heteroaryl replaced, each Y is a non-interfering substituent, and each x is, independently, 0, 1 or 2, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of its stereoisomers. Use according to any one of claims 1 to 11, wherein said medicament further comprises a further form of treatment for insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy or hypertriglyceridemia. The use according to claim 12, wherein the therapeutically effective amount of said further form of treatment, when administered in combination with a compound according to the invention, may be less than the amount of said further form of treatment which would be therapeutically effective if administered to the patient alone. The use according to claim 12, wherein said further form of treatment is insulin. Use according to claim 12, wherein said further form of treatment is an insulin analog. Use according to any one of claims 14 or 15, wherein the therapeutically effective amount of insulin or insulin analog, administered in combination with a compound of the invention, may be less than the amount of insulin or insulin analog that would therapeutically be effective when administered to the patient alone. Use according to any one of claims 1 to 11, wherein said further medicament comprises a second of the compounds used in claims 3-11. 18. Use according to any one of claims 1 to 4, wherein the compound is Compound 1 Use according to any one of claims 1 to 4, wherein the compound is Compound 2 Use according to any one of claims 1 to 4, wherein the compound is 21. Pharmaceutical composition comprising an insulin receptor activating compound or a pharmaceutically acceptable salt thereof, wherein said compound is not insulin, and a pharmaceutically acceptable vehicle for the treatment of a disease induced by the use of an HIV protease inhibitor . Pharmaceutical composition comprising a compound according to any one of claims 3 to 11 or 18 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle for the treatment of a disease induced by the use of an HIV protease inhibitor. 23. A process for the treatment of a disease induced by the use of an HIV protease inhibitor, comprising the administration of a therapeutically effective dose of an insulin receptor activating compound or a pharmaceutically acceptable salt thereof, wherein said compound it is not insulin. The process according to claim 23, wherein the insulin receptor activating compound is a compound according to any one of claims 3 to 11 or 18 to 20, or a pharmaceutically acceptable salt thereof.