MXPA00012389A - Therapeutic biaryl derivatives - Google Patents

Abstract

The present invention relates to therapeutic biaryl derivatives of formula (I), and pharmaceutically acceptable derivatives thereof;wherein R1 is a phenyl, naphthyl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1-6alkyl, nitro, cyano, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHSO2R6, where each R6 is independently hydrogen or C1-4alkyl;R2 is hydrogen or C1-6alkyl;X is oxygen, sulfur, -NH, or -NC1-4alkyl;R3 is cyano, tetrazol-5-yl, or -CO2R7 where R7 is hydrogen or C1-6alkyl;R4 and R5 are independently hydrogen, C1-6alkyl, -CO2H, -CO2C1-6alkyl, cyano, tetrazol-5-yl, halogen, trifluoromethyl, or C1-6alkoxy, or, when R4 and R5 are bonded to adjacent carbon atoms, R4 and R5 may, together with the carbon atoms to which they are bonded, form a fused 5 or 6 membered ring optionally containing one or two nitrogen, oxygen, or sulfur atoms;and Y is N or CH, to processes for their preparation and their use in the treatment of diseases susceptible to amelioration by treatment with a beta-3 adrenoceptor agonist.

Description

THERAPEUTIC BIARILY DERIVATIVES FIELD OF THE INVENTION The invention describes a new class of chemical compounds and their use in medicine. In particular, the invention describes biaryl derivatives, the methods for their preparation, the pharmaceutical compositions containing them and their use as agonists in the atypical beta adrenoceptors (also known as adrenocept ores-3-beta).

BACKGROUND OF THE INVENTION The athero-adrenoceptors beta belong to the family of adr enocept ore s which mediate the physiological actions of adrenaline and noradrenaline of hormones. Such receptors have been described, for example, in J R S Arch et al. , Na ture, 309, 163-165 '(1984); C ilson et al. , Eur. J. Pharmacol. , 100, 309-319 (1984); L J emorine et al. , Science, 245, 1118-1121 (1989); and A, Bianchetti et al. , Br. J. Pharmacol. , 100, 831-839 (1990).

Fenet anolamine derivatives having an activity on atypical beta adrenoceptors are described, for example, in European Patent Applications EP-A-0455006 and EP-A-0543662. The subtypes of adr enocept ore s, a -.-, a2- ß? ~. ß2- and ß3- (atypical) can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents that stimulate or block these receptors (but not ß3) are used simultaneously in clinical medicine. More recently, emphasis has been placed on the selectivity of the specific receptor in order to reduce side effects caused, in part, by interactions with other receptors. It is well known that adr enocept ore s beta appendixes occur in the adipose tissue and in the gastrointestinal tract. Atypical beta adrenoceptor agonists are found to be particularly useful as anti-diabetic agents. Compounds that have an atypical beta adrenoceptor agonist activity are also described as being useful in the treatment of hyperglia, as growth promoters in the animals, as inhibitors of blood platelet aggregation, as positive inotropic agents, and as anti-erosclerotic agents, and are useful in the treatment of glaucoma.

BRIEF DESCRIPTION OF THE INVENTION Briefly, in one aspect, the invention therefore provides compounds of formula (I) and pharmaceutically derivatives thereof: (i) wherein: R 1 is a phenyl, naphthyl, pyridyl, thiazolyl, f-enoxyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, Ci-Cβ alkoxy, alkyl Ci-Cβ, nitro cyano, hydroxymethyl, trifluoromethyl, -NR6R6 and -NHS02R6, wherein each R6 is independently hydrogen or C i -C4 alkyl; R 2 is hydrogen, or C 1 -C 6 alkyl, X is oxygen, sulfur, -NH, or -N C 1 -C 4 alkyl, R 3 is cyano, tetra zol-5 i 1, or -C0 2 R 7 wherein R 7 is hydrogen or Ci-Cß alkyl, R4 and R5 are independently hydrogen, C i -C 6 alkyl, -C02H, -C02 C i -C 6 alkyl, cyano, tetrazol-5-yl, halogen, trifluoromethyl, or Ci-C β alkoxy. or wherein R4 YA are attached to the adjacent carbon atoms, R4 and R5 can, together with the carbon atoms to which they are attached, form a ring provided with optionally fused 5 to 6 members containing one or two sulfur atoms , oxygen or nitrogen, and Y is N or CH. The compounds of the present invention are of use in medical therapy. Preferably the compounds of this invention are agonists for the human adrenoceptor-3-beta rβ3"). More preferably, the compounds of this invention are selective agonists for β3 In another aspect, the present invention provides a pharmaceutical formulation comprising ur compound of the invention, or a pharmaceutically acceptable derivative thereof, and one or more pharmaceutically acceptable carriers. In another aspect of the invention, it provides a method for the prevention or treatment of clinical conditions or diseases susceptible to an improvement by the administration of an atypical beta adrenoceptor agonist., which comprises the administration of an effective amount of a compound or composition of this invention, or a pharmaceutically acceptable derivative thereof. In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of conditions or diseases susceptible to an improvement by the administration of an atypical beta adrenoceptor agonist.

DETAILED DESCRIPTION OF THE INVENTION As used herein the terms "alkyl" and "alkoxy" mean a straight open alkyl group or branched or an alkoxy group respectively, which contains the indicated number of carbon atoms. For example, Ci-Ce alkyl means a straight or branched open alkyl containing at least 1 and at most 6 carbon atoms. Preferably, R 1 is a phenoxymethyl or phenyl optionally substituted by one, two or three substituents selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, nitro, cyano, hydroxymethyl and trifluoromethyl. More preferably, R1 is a phenoxymethyl or phenyl substituted by a chlorine, fluorine atom or a group is preferably located in the meta position. More preferably, R1 represents a phenyl substituted by a chlorine atom located in the met a position. Preferably, R 2 is a hydrogen or a methyl, more preferably R 2 is hydrogen. Preferably, X is -NH or -NCH3. More preferably, X is -NH. Preferably, R3 is C02H. Preferably, R3 is attached to the meta or para carbon atom to the attached phenyl ring, more preferably to the meta position.

Preferably, R and R are independently hydrogen, methyl, trifluoromethyl, C02H or, where R4 and R5 are attached to the adjacent carbon atoms, R4 and R5 together with the carbon atoms to which they are attached form a fused dihydrofuran ring. More preferably, R4 and R5 are independently hydrogen, methyl, or trifluoromethyl. Preferably at least one of R4 and R5 is hydrogen. More preferably, both R4 and R5 are hydrogen. Preferably Y is CH. Particularly preferred compounds of the invention include those wherein each variable in Formula (I) is selected from the preferred groups for each variable. The most preferred compounds of the invention include those where each variable in Formula (I) is selected from the most preferred groups of each variable. It will be appreciated that the above compounds of Formula (I) may contain optically active centers. The individual isolated isomers and mixtures thereof, which include the racemates, are all within the scope of the present invention. Typically, where R 2 is C 1 -C 6 alkyl, mixtures of di emers of the compounds of Formula (I) can be obtained, which are enriched with more than or equal to 80 wt% of the day of the reomer. Particularly preferred compounds of Formula (I) are those in which the asymmetric carbon atoms in the group -CH (OH) - and the group -CH (R2) - are both in the (R) -configuration. Formula (I) of the present invention include: (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1, 1] methyl ester '-biphenyl] -3-carboxylic; Dimethyl ester of (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -2,4-dicarboxylic acid; (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1' -biphenyl] -2-methyl-5-methyl ester -carboxylic; Dimethyl ester of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3, -dicarboxylic acid; Methyl ester of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1-biphenyl] -3-chloro-4 acid -carboxylic; (R) -3 '- [[2 - [[2- (3,5-dichlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid methyl ester , (R) -3 '- [[2- [[2- (3,5-Dichloro-enyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid; (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid; 2-Methyl ester of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1' -biphenyl] -2, 4-methyl ester -dicarboxilic; (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -2,4-dicarboxylic acid; (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -2-methyl-5-carboxylic acid; Acid (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-chloro-4-carboxylic acid; Acid () -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amir. ] ethyl] amino] - [1,1'-biphenyl] -3,4 -dicarboxylic; (R) -3 '- [[2- [(2-Hydroxy-3-phenoxypropyl) amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid; Acid R) -3 '- [2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amydazole] ethoxy] - [1,1'-biphenyl] -3-carboxylic acid; 3 '- [[2R- [[2- (3-chlorophenyl) -2R-hydroxyethyl] amyr. or] propyl] amino] - [1,1'-biphenyl] -4-carboxylic; 3 '- [[2R - [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] - [1,1'-biphenyl] -2-carboxylic acid; 3 '- [[2R - [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] - [1,1'-biphenyl] -2,4-dicarboxylic acid; 5- [3 - [[2R - [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] phenyl] -3-pyridinecarboxylic acid; 2- [3 - [[2R - [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] phenyl] -3-pipdinecarboxylic acid; (R) -5- [3 - [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -2,3-dihydro-7-benzofurancarboxylic acid; Ac gone R '5- [3- [[2- [[2- (3-chlorophenyl-hydroxyethyl] amino] ethyl] amino] phenyl] -3-pyridinecarboxylic acid (R) -2- [3 - [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -4-pyridinecarboxylic acid (R) -6- [3 - [[2 - [[2- (3-chlorophenyl)] - 2-hydroxyethyl] amino] ethyl] amino] phenyl] -2-pyridinecarboxylic acid; (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3- (5-tetrazolo); (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carbonitrile; and the pharmaceutically acceptable derivatives of the same. As used herein "a pharmaceutically acceptable derivative" means a pharmaceutically acceptable salt, ester, or salt of the ester, which upon administration to the container, is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue of the same. It will be appreciated by those skilled in the art that the compounds of formula (I) can be modified to provide pharmaceutically acceptable derivatives thereof to any of the functional groups in the compounds of Formula (I). Such derivatives of particular interest are the compounds modified in the carboxyl function, hydroxyl functions or in the amino groups. It will be appreciated by those skilled in the art that pharmaceutically acceptable derivatives of the compounds of formula (I) can be derivatized in more than one position. The pharmaceutically acceptable derivatives that are preferred from the compounds of Formula (I) are the pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salts of the compounds of Formula (I) include those derived from inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, tartaric, acetic, citric, phonoic, formic, benzoic, malonic, phthalene-2-phonic and benzene sulfonic acid. Other acids such as oxalic, while they themselves are not pharmaceutically acceptable, may be useful as intermediates in obtaining compounds of the invention and their pharmaceutically acceptable acid addition salts. The salts derived from the bases Suitable include (for example magnesium), ammonium and salts of NR4 + (where R is an alkali C? _).

The compounds of Formula (I) act as agonists in the atypical adrenoceptors beta and as such are useful in the treatment of clinical conditions susceptible to an improvement by the administration of an atypical beta adrenoceptor agonist. Such conditions include hyperglycemia, hyper-idiopathic obesity, irritable bowel syndrome and its associated pain, mobility dysfunction, excessive gastrointestinal decrease, nonspecific diarrhea, neurogenic inflammation, intraocular pressure regulation, tr igl i ce r idemi a, diabetes, for example, diabetes mellitus not dependent on insulin (NIDDM or Type 2) such as the obese NIDDM and non-obese NIDDM, diabetic complications such as retinopathy, nephropathy, neuropathy, cataracts, coronary heart disease and arteriosclerosis, osteoporosis; and inflammatory gastrointestinal disorders. They are also of use in increasing the concentration of high density lipoprotein (HDL) cholesterol and the decrease of the triglyceride concentration in the blood serum, especially the serum of human blood, and are therefore of potential use in the treatment and / or prophylaxis of atherosclerosis. They can also be useful for the treatment of hyperinsulinemia, depression, muscle exhaustion, and urinary incontinence. They can also be useful in the preparation of wound healing medicines. References in this specification for treatment include prophylactic treatment as well as symptom relief. In a further aspect, the invention provides the use of a compound of general Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a condition amenable to improvement by a beta-adrenoceptor agonist. atypical. While it is possible that, for use in therapy, a compound of the invention can be administered as the unrefined chemical is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus provides a pharmaceutical formulation comprising a compound of Formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers and optionally, other therapeutic and / or prophylactic ingredients. The carrier (s) or excipient (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not being harmful to the recipient thereof. The compounds for use according to the present invention can be formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose) . Pharmaceutical compositions for oral administration may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as linking agents. (for example cornstarch pr oge 1 a t ini zed, methylcellulose, polyvinylpyrrolidone or hydroxypropyl 1); fillers (for example lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (e.g., potato starch, or sodium starch glycolate); or wet agents (for example sodium lauryl sulfate). The tablets can be covered by methods known in the art. Liquid preparations for oral administration may take the form of, for example, syrups or suspensions, or may be presented as a dry product for constitution with water or other acceptable vehicles before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example sorbitol, syrup, cellulose derivatives or hydrogenated edible gases); emulsifying agents (for example, almond oil, oily esters, alcohol ethyl, or fractionated vegetable oils); and preservatives (for example, methyl or propi 1-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring agents, colorants and sweeteners as appropriate. Preparations for oral administration can be suitably formulated to provide controlled release of the active compound. For oral administration the compositions may take the form of tablets or lozenges formulated in a conventional manner. The compounds according to the present invention can be formulated for administration by injecting, for example, large pills or by continuous infusion. The formulations for injection can be presented in the form of unit doses for example, in ampoules or in multi-dose containers, with an added condom. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as agents. dispersants, stabilizers and / or suspensions. Alternatively, the active ingredient may be in the form of a powder for constitution with a suitable vehicle, for example sterile pyrogenic water, before use. The compounds according to the present invention can also be formulated in rectal compositions such as suppositories or retention creams, for example, containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention can be formulated with polymeric and hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives. Suitable therapeutic ingredients which can be formulated with compounds of the invention, together with one or more pharmaceutically acceptable carriers or excipients, which include ingredients which can be used in the same clinical conditions as those listed herein for the atypical adrenoceptors beta agonists. . Such ingredients may include, for example, PPAR-gamma agonists. A proposed dose of the compounds according to the present invention for administration to a human (approximately 70 kg body weight) is 0.1 mg to 1 g, preferably 1 mg to 100 mg of the active ingredient per unit dose, expressed as the weight of the free base. The unit dose can be administered, for example, from 1 to 4 times per day. The dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations for the dose depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and route of administration are left to the discretion of the compet ent physician. The compounds of the invention can be prepared by any of the processes known in the art for the preparation of similar compounds. For example, according to a first process (A), the compounds of Formula (I) can be prepared from a compound of Formula (II) • (H) wherein P1 and P2 are suitable protecting groups for the oxygen and nitrogen groups respectively, by the deprotection of P1 and P2 under suitable conditions such as treatment with an acid, for example, the acid aqueous hydrochloric acid in a suitable solvent such as dioxane. As an additional process (B), the compounds of Formula (I) can be prepared from other compounds of Formula (I). For example, a compound of Formula (I) wherein R3 is C02H can be prepared from a corresponding ester by hydrolysis, for example by base hydrolysis with a reagent such as lithium hydroxide in a solvent such as tetrahydrofuran. The compounds of Formula (II) wherein X = NH can be prepared by the reaction of a compound of Formula (III) with a compound of Formula (IV): ("I) (IV) wherein P1 and P2 are suitable protecting groups for the oxygen and nitrogen groups respectively.

The compounds of Formula (II) wherein R3 is tetra zol -5-i can be prepared from the compounds of Formula (II) where R3 is cyano, by treatment with, for example, the azide t rimet ilsilyl in such a solvent like toluene.

As an additional process (c), the preparation of the compounds of Formula (II), as defined above, followed by step (A) can be combined without the purification of intermediates. The compounds of Formula (III) are described in WO 95/33724 or can be prepared by standard methods described herein. The compounds of Formula (IV) can be prepared from the compounds of Formula (V). The conversion methods of the Formula compounds (V) Compounds of Formula (IV) are well known and include, but are not limited to, the treatment of a compound of Formula (V) with tin (II) chloride in a suitable solvent such as ethyl acetate or stirring under an atmosphere of hydrogen in a suitable solvent such as tetrahydrofuran in the presence of a suitable catalyst such as palladium 0) in carbon (V) The compounds of Formula (V) can be prepared by the reaction of a compound of Formula (VI) with a compound of Formula (VII) according to the method of Thompson (J. Org. Ch em 1984, 49, 5237) where Z is halogen or triflate.

(VI) (VII) According to another process (D) the compounds of Formula (I) can be prepared by the reacting a compound of Formula (VII) with a compound of Formula (IX) in a suitable solvent such as methyl sulfoxide.

(VIII) (IX) The compounds of Formula (IX) where X = NH 2 can be prepared by the reaction of the compounds of Formula (X) with compounds of Formula (IV), in the presence of a suitable reducing agent followed by the removal of P 2 using standard methods .

(X) A compound of Formula (IX) can also be prepared from a compound of Formula (XI) in the presence of a suitable reducing agent such as borate in tetrahydrofuran followed by removal of P2 using standard conditions.

(XI) A compound of Formula (XI) wherein X = NH2 in turn can be prepared by the reaction of a compound of Formula (IV) with a compound of Formula (XII), in the presence of a suitable reducing agent such as hydrochloride of 1- (3-dimethyl and lamino propyl) -3-ethylcarbodiimide.

(Xii) A compound of Formula (IX) wherein X is 0 can be prepared by the reaction of a compound of Formula (XIII) with a suitable base such as potassium carbonate followed by treatment with a compound of Formula (XIV), where R3 is not C02H followed by the removal of P2. Referring to Formula (XIII), LG is a leaving group, preferably a halogen.

(XIII) (XIV) A compound of Formula (XIV) can be prepared by treating a compound of Formula (XV) where R3 is not C02H, with a suitable reagent such as boron tribromide. A compound of Formula (XV) can in turn be prepared by the treatment of 3-me t-oxy-phenyl-boronic acid with a compound of Formula (VII) in the presence of a suitable catalyst according to the method described above.

(XV) The compounds of Formula (XV) can be prepared by the reaction of a compound of Formula (XVI) with a compound of Formula (VII) according to the method of Thompson (J. Org. Ch., 1984, 49, 5237) in where Z is halogen or trilfate.

(XVI) (Vil) Suitable reducing agents for use in the reactions include hydrogen in the presence of a catalyst, such as a noble metal catalyst, for example, palladium, platinum or platinum oxide, Raney-Nickel or hydride, reducing agents such as borohydrides, for example, sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride. Suitable reaction conditions will be readily apparent to those skilled in the art and are further illustrated by the accompanying examples. The protecting groups used in the preparation of the compounds of Formula (I) can be used in conventional manner. See for example, "Protective Groups in Organic Chemistry", Ed. J.F. W McOmie (Plenum Press 1973) or "Protective Groups in Organic Synthesis". By Theodora W Greene and P M G Wuts (John Wiley and Sons 1991). The amino-protecting groups with entionals may include, for example, aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups, such as N-benzyloxycarbonyl or t -bu t oxycarbonyl. Conventional oxygen protecting groups can include, for example silyl groups, alkyl such as trimethylsilyl, or tert-butyl dimethylsilyl; alkyl ethers such as tetrahydropyranyl, or tert-butyl; or esters such as acetate. The removal of any present protecting group can be carried out by conventional procedures. The atypical adrenocept or-bet agonists are compounds that demonstrate a pharmacological response measured in the atypical beta adrenoceptors. This activity is measured as the ability to stimulate lipolysis by rat adipocytes at submicromolar concentrations in a response that is resistant to blockage by standard beta-adrenoceptor blocking drugs such as propanol. Other useful methods of identifying an atypical beta adrenoceptor agonist involve measuring the activity of atypical beta adrenoceptors in the lower esophagus isolated from the rat. Typically in this test a compound of general Formula (I) for use according to the present invention has a molar proportion of equipotential (EPMR) relevant to isoprenaline of less than 30. The test of the esophagus of the rat as described by Fu rd e t a l. , B r J. Ph a rm a co l. , 105 (suppl). 235P, 1992. The relative potency of each test compound (EPMR) is compared with isoprelamine as follows: EPMR = agoni sta EC 5 (isoprelanine EC5 ( where EC5o is the molar concentration of the agonist that produces 50% of the maximum possible response for the agonist. A particularly useful method for the agonist activity determined in human atypical beta adrenoceptors involves the use of Chinese hamster ovary (CHO) cells transfected with human adrenocept or-3-beta ta according to the method of determining the selectivity of the compounds of the invention in the three receptors.

Cell culture Method 1 The general guidelines of cell culture are observed (Fershney, R.A. (1987) animal cells. A basic technique manual Wiley-Liss, Ine N.Y.). A standard culture cell incubator (37 ° C C02 5% in air, 95% relative humidity) is used. H ß CHO cells grow in DMEM / F12 (with pi r oxidine * HCl, 15 mM HEPES, L-glutamine), which supplants inactivated heat 10% FBS, 500 mg / ml G418, 2mM L-glutamine, 100 units of penicillin, G and 100 μg of streptomycin sulfate. A flask with confluent trypsin cells and resuspended in the above medium at a concentration of 30-40,000 cells / 100 μl and placed in 96 well flat bottom plates. The cells are then used for the test, within 18-24 hours. The medium is aspirated from each plate, and replaced with 18 μl of DMEM / F12 with IBMX500 mM. Antagonists, which are required, are added at this stage. The plate is then placed again in the incubator for 30 minutes. The medications are then added to the plates (20 μl, 100 X the final concentration required) for 60 minutes. The answers are determined by measuring the cAMP levels of a sample 20 μl of extracellular media using a radio immunoassay based on the proximity of scintillations (NEN instant dishes). The CHO-6-CRE luciferase cell lines which stably express the hß3 receptors are seeded at 30,000 cells / plate for 24 hours in DMEM / F12 containing 10% FBS. Cell media is removed and replaced with DMEM / F12 buffer (180 μl) containing IBMX 300 M and lmM ascorbic acid for 30 minutes prior to compound addition. The vehicle or agonist (20 μl) is added and incubated at 37 ° C for 60 minutes. At the end of the incubation period, samples from the extracellular media are removed by a direct assay on the instantaneous cAMP (NEN) plates. As used herein, a compound is considered an agonist for hß3 if the compound stimulates the accumulation of extracellular cAMP with CHO-6CRE-luciferase cells expressing hß3. Preferably, the compounds of this invention have an EC5o of no more than 100 nM to hß3. More preferably, the compounds of this invention have an EC50 at most of InM to hß3. The relative potency of a hß3 agonist can be compared to its potency to stimulate the accumulation of extracellular cAMP with CHO-6CRE luciferase cells expressing hß2 and hßi. Preferably, the compounds of this invention are at least 100 times more potent at hß3 than at hß2 and hßi. More preferably, the compounds of this invention are at least 300 times more potent at hß3 than at hß2 and hßi.the compounds of Examples 9, 10, 11, 12, 13, 14, 15, 16, 17, 20, 21 , 22, 23 and 24 have an EC50 of at most 100 nM to hß3 and are at least 100 times more potent at hß3 than at hß2 and hßx. Examples 10, 13, 16, 20 and 24 have an EC50 of at least InM and are greater than 300 times selective to hß2 and hßi.

The invention The invention is further illustrated by the following intermediates and examples. All temperatures are in degrees centigrade. The HPLC characterization is carried out where specified using a Dynamax-60a C18 83-201-C, with a 25 cm X 4.6 mm column, eluting with CH3CN 5-40% in H20 with 0.1% TFA buffer, with a program time of 30.0 minutes and a flow rate of 1.5 mL / min. Retention times are expressed as tr in minutes. The optical rotation values are expressed as values [CC] D. The mass spectra (ms) are obtained using an electrostatic analysis i or (positive or negative ion). H nmr is carried out in deuterated chloroform, until otherwise indicated.

Intermediate 1 4-bromo-2-chloroben zoat or methyl Anhydrous methanol (45 ml) is added acetyl chloride (1.9 ml) for 2 minutes. The mixture, which starts to be slightly exothermic and develops gas, is stirred for 15 minutes. The 4-bromo-2-chlorobenzoic acid (3.0 g) is added in one portion and the mixture is heated at reflux for 16 hours. The mixture is allowed to cool to room temperature and the solvent is removed with a rotary evaporator. The residue is divided between saturated aqueous sodium bicarbonate and diethyl ether. The organic layer is separated, dried with sodium sulfate, filtered and concentrated to obtain the title compound as a white solid (2.89 g). n.m.r. d values including 3.90 (s, 3H), 7.44 (dd, 1H), 7.62 (d, 1H), 7.70 (d, 1H). p.f. 28-30 ° C.

They are prepared in a similar manner: Intermediate 2 3 -bromo- -me t i lbenzoat or methyl as a pale yellow oil (2.61 g); n.m.r. d- values that include 2.40 (s, 3H), 3.90 (s, 3H), 7.25 (d, 1H), 7.80 (d, 1H), 8.15 (s, 1H), of 3-bor orno-4-me acid ti lben zoi co (2.63 g) and acetyl chloride (1.8 ml).

Intermediate 3 4 -bromof t dimethyl dimethyl ether as a pale yellow oil (3.1 g); n.m.r. (DMSO-d6) d values including 3.79 (s, 3H), 3.80 (s, 3H), 7.68 (d, 1H), 7.86 (dd, 1H), 7.89 (d, 1H), acid 4 -br omof ta 1 i co (3.0 g) and acetyl chloride (1.8 ml) in anhydrous methanol (50 ml).

Intermediate 4-dimethyl bromoisophthalate as a white solid (3.09 g); n.m.r. d values including 3.92 (s, 3H), 3.94 (s, 3H), 7.73 (d, 1H), 7.94 (dd, 1H), 8.42 (d, 1H), of 4-bor omoi so fta 1 ico acid ( 3.0 g) and acetyl chloride (1.8 ml) in anhydrous methanol (50 ml).

Intermediate 5 Methyl ester of 3-bromo-5-pyridinecarboxylic acid as a pale yellow solid (2.97 g); n.m.r. (DMSO-de) d values including 3.89 (s, 3H), 3.44 (s, 1H), 8.97 (s, 1H), 9.04 (s, 1H), of 3-bromo-5-pyridinecarboxylic acid (3.00 Intermediary 6 2-Hydroxy-3-pyridinecarboxylic acid methyl ester as a white solid (1.58 n.m.r. (DMSO-de) d values that include 3.71 (s, 3H), 6.25 (t, 1H), 7.64 (dd, 1H), 8.04 (dd, 1H), 12.08 (bs, 1H), of 2-hydroxy-3-pyridinecarboxylic acid (2.50) Intermediate 7 2- t -methyltrifluoromethanesulfonyl) oxy-3-pyridinecarboxylic acid methyl ester To a solution of stirred and cooled 2- (trifluoromethanesulfonyl) oxy -3-pyridinecarboxylic acid methyl ester (1.12 g) (-78) ° C) in dichloromethane is added di i sopropí lamina (1.04 g) dropwise. The mixture is stirred for 20 minutes and then trifluoromethanesulfonic anhydride (2.18 g) is added dropwise. After 30 minutes the mixture is quenched with water, warmed to room temperature and extracted with dichloromethane. The organic layer dries with magnesium sulfate. The solvent is removed under reduced pressure and the residue is analyzed by chromatography on silica gel, eluting with ethyl acetate in hexane 1: 4 to give the title compound (1.66 g) as a white solid. MS electrorrocio (positive ion): (M + H) 307 n.m.r. (DMSO-de) d values that include '3.90 (s, 3H), 7.78 (dd, 1H), 8.58 (dd, 1H), 8.69 (dd, 1H).

Intermediate 2-bromo-4-pyridinecarboxylic acid ethyl ester To a suspension of 2-bromo-4-pyridinecarboxylic acid (prepared according to the method of Ashimori, Ch em, Ph a rm B ull, 38 (9) 2446 -2458 (1990)) in toluene: pure ethanol 2: 1 (45 ml) is added sulfuric acid (0.75 ml). The mixture is heated to reflux for 16 hours, the mixture is poured into a mixture of saturated aqueous sodium bicarbonate and extracted with chloroform (3 times). The chloroform extracts are dried combined with magnesium sulfate, they are filtered and concentrated to produce the crude product as a yellow oil. Purify by chromatography on silica gel and elute with 9: 1 hexane: ethyl acetate to obtain the title compound (900 mg) as a clear, colorless oil. N.m.r. d which include 1.39 (t, 3H), 4.40 (q, 2H), 7.79 (d, 1H), 8.02 (s, 1H), 8.50 (d, 1H).

Intermediate 9 2-bromo-6-pyridine-carboxylic acid 2-bromo-6-me t i 1 pyridine (5.0 g) and potassium permanganate (4.74 g) are added to the deionized water (75 ml). After refluxing for 1 hour another portion of potassium permanganate (4.74 g) in deionized water (75 ml) is added. The mixture is heated to reflux for an additional 5 hours and filtered through celite. The filtrate is acidified with 6N hydrochloric acid and the product precipitates as a white solid. The solid is collected by suction filtration and the filtrate is extracted with ethyl acetate, dried with magnesium sulfate, it is filtered and concentrated to produce more title product (2.65 g in total). p.f. 189-191 ° C.

Intermediate 10 Ethyl ester of 2-bromo-6-pyridine-carboxylic acid Sulfuric acid (1.46 ml) is added to a mixture of 2-bromo-6-pyridine-carboxylic acid, ethanol (15 ml) and toluene (30 ml). The reaction is heated to reflux for 16 hours. The mixture is divided between the chloroform and a saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted with chloroform (2X) and the combined organic layers are dried with sodium sulfate, filtered and concentrated to produce a cloudy orange oil. The oil is purified by chromatography with silica gel with hexane: ethyl acetate 9: 1. The title product is obtained as an oily white solid (1.31 g).

N.m.r. (CD3OD) d including 1.39 (t, 3H), 4.41 (q, 2H), 7.79 (d, 2H), 7.85 (t, 1H), 8.08 (d, 1H).

Intermediate 11 Methyl ester of 3'-nitro- [1, 1'-biphenyl] -4-carboxylic acid It is added to a stirred mixture of methyl 4-bromobenzoate (1.00 g) and 3-nitrophenylboronic acid ( 800 mg) in dioxane (20 ml) palladium (0) tetrakis (triphenylphosphine) (165 mg) and solid sodium carbonate (710 mg). The mixture is heated at 85 ° C overnight, cooled to room temperature and partitioned between dichloromethane (100 ml) and 2M aqueous sodium carbonate (50 ml) containing concentrated ammonium hydroxide (5 ml). The aqueous layer is also extracted twice with dichloromethane. The combined organic layers are washed with brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue is absorbed on silica and analyzed by chromatography with silica gel eluting with ethyl acetate in hexane 6:94 to give the title compound (198 mg) as a white solid. N.m.r. (DMSO-d6) d including 3.88 (s, 3H), 7.79 (t, 1H), 7.95 (dd, 2H), 8.07 (dd, 2H), 8.24 (m, 21H), 8.504 (t, 1H).

They are prepared in a similar manner: Intermediate 12 Methyl ester of 3-nitro- [1, 1 '-biphenyl] -2-carboxylic acid as a white solid (1.81 g); N.m.r. (DMSO-d6) d which include 3.61 (s, 3H), 7.51 (d, 1H), 7.58 (t, 1H), 7.69 (m, 3H), 7. 88 (d, 1H), 8.24 (d, 1H); of 2 -br omoben zoa t or methyl (1.53 g), tetrakis (tri-f-enylphosphine) palladium (0) (270 mg) and 3-nitric oxide t-boronic acid (1.44 g).

Intermediate 13 Methyl ester of 3 '-n i t r o- [1,1' -biphenyl] -3-carboxylic acid as a brown solid (2.28 g); n.m.r. d values include 3.96 (s, 3H), 7.57 (t, 1H), 7.64 (t, 1H), 7.81 (d, 1H), 7.94 (d, 1H), 8.09 (d, 1H), 8.23 (dd, 1H), 8.30 (s, 1H), 8.48 (t, 1H), mp, 88-90 ° C; from 3-bromoben zoa t or methyl (2.0 g), tet rachis (trif enil fos fines) palladium (0) (348 mg) and 3-nitrophenylbenzoic acid (1.9 g).

Intermediate 14 3- (3-Nitrophenyl) -5-pyridinecarboxylic acid methyl ester Intermediate 14 is prepared as a tan solid (296 mg); Found test: C 60.61; H 3.93; N 10.78% C? 3H10N2O4 requires C 60.47; H 3.90; N 10.85%; from the methyl ester of 3-bromo-5-pyridinecarboxylic acid (1.00 g) and 3-ni t-rofeni lboronic acid (785 mg) tet rachis (triphenylphosphine) palladium (0) (164 mg).

Intermediary 15 2 - (3-ni t rof eni 1) - 3-pyridinecarboxylic acid methyl ester as a tan solid (301 mg) n.m.r. (DMSO-d6) d values including 3.69 (s, 3H), 7.75 (dd, 1H), 7.94 (dd, 1H), 8.29 (m, 3H), 8.86 (dd, 1H); from 2- (trifluoromethanesulfonyl) oxy-3-pi, idinecarboxylic acid methyl ester (506 mg), 3-nitric acid (325 mg) and tet rachys (fine tri-phosphate) ) palladium (0) (70 mg).

Intermediary 16 Dimethyl acid ester of 3'-nitro- [1, 1 '-biphenyl] -3,4-dicarboxylic acid as a brown solid (1.6 g); n.m.r. d values that include 3.93 (s, 3H), 3.94 (s, 3H), 7.65 (t, 1H), 7.78 (dd, 1H), 7.86 (d, 1H), 7.92-7.95 (m, 2H), 8.26 (dd, 1H), 8.46 (t, 1H); from 4-bromine to dimethyl ether (1.80 g), rachis tet (trif enylphosphino) palladium (0) (246 mg) and 3-nitrophenolylboronic acid (1.3 g).

Intermediate 17 Methyl ester of 3 '-ni t r o - [1,1'-biphenyl] -3-chloro-4-carboxylic acid as a brown solid (2.03 g); n.m.r. d values including 3.96 (s, 3H), 7.56 (dd, 1H), 7.65 (t, 1H), 7.71 (d, 1H), 7.91 (d, 1H), 7.97 (d, 1H), 8.27 (d, 1H), 8.47 (m, 1 H); starting from 4-bromo-2-c lor methyl ester (2.0 g), tet raqui s (t ri feni 1 fos fine) palladium (0) (299 mg) and acid 3-nitric phenol lboroni co ( 1.6 g).

Intermediate 18 Methyl ester of 3 '-ni t r o- [1,1'-biphenyl] -2-methyl-5-carboxylic acid as a tan solid (605 mg); Found assay: C, 66.36; H, 4.87, 5.15 C15H13N? 04 requires C, 66.41; H, 4.83, N, 5.16; from methyl 3-bromo-4-methylbenzoate (2.3 g) in toluene (28 ml), tet rachis (triphenylphosphino) palladium (0) (381 mg) and 3-nitophenylbenzoic acid (2.03) g) in methanol (7 ml).

Intermediate 19 Dimethyl acid ester of 3'-n-t- [1, 1'-biphenyl] -2,4-dicarboxylic acid as a tan solid (880 mg); MS electrorroium (positive ion): (M + Na) 338; from 4-br omoi s of ta dimetil to (1.26 g), 3-nitric oxide (795 mg) and tet raqui s (tri-phenyl-fine) palladium (0) (167 mg) .

Intermediate 20 5- (3-Nitrophenyl) -2,3-dihydro-7-benzofurancarboxylic acid methyl ester as a pale yellow solid (650 mg); p.f. 53-57 ° C; from the methyl ester of 5-bromo-2,3-dihydro-7-ben zof urancarboxylic acid (1.0 g), tet rachis (trif enylphosphino) palladium (0) (103 mg), 2M sodium carbonate (7.0 ml) and 3-ni t-rofeni lboronico acid (741 mg) in methanol (5 ml).

Intermediary 21 3- (3-Nitrophenyl) -5-pyridinecarboxylic acid ethyl ester as a pale yellow solid (400 mg); n.m.r. d values that include 1.5 (t, 3H), 4.5 (q, 2H), 7.75 (t, 1H), 8.0 (d, 1H), 8.3 (d, 1H), 8.6-8.5 (m, 2H), 9.0 ( s, 1 H), 9.3 (s, 1 H); from the ethyl ester of 3-bromo-5-pyridine carboxylic acid (985 mg) in toluene (15 ml), tet rachys (fine tri-phenyl) palladium (0) (161 mg) and 3-naphthyl acid tr of eni lbor oni co (860 mg).

Intermediary 22 2- (3-Nitrophenyl) -pyridinecarboxylic acid ethyl ester as a white solid (355 mg); Electrorrocy MS (positive ion): (M + H) 272.8; from the ethyl ester of 2-bromo-4-pyridinecarboxylic acid (900 mg), tet raqui s (tri-phenyl-1-phos) palladium (136 mg), and 3-n-t-phenyl-polonic acid (783 mg).

Intermediary 23 Methyl 3- (3-methoxyphenyl) -benzoate as a clear, colorless liquid (3.34 g); XH NMR d values including 3.86 (s, 3H), 3.93 (s, 3H), 6.91 (dd, 1H), 7.13 (s, 1H), 7.76 (d, 1H), 8.00 (d, 1H), 8.26 ( s, 1H), from methyl 3-bromobenzoate (5.82 g), tet rachis (tri-pheni-1-fin) palladium (1.0 g) and 3-methoxy-phenyl-lyronic acid (5.0 g).

Intermediate 24 3'-nitro- [1,1] -biphenyl] -3-carbonitrile as a yellow solid (1.96 g), m.p. 169-173 ° C; from 3-bromoben zoni tri lo (2.0 g) in toluene (20 ml), 3-nitrofenylboronic acid (2.2 g), and tet raqui s (tri phenyl fos) palladium (0) (381) mg) in methanol (5 ml).

Intermediary 25 6- (3-Nitrophenyl) -2-pyridinecarboxylic acid methyl ester and 6- (3-nitrophenyl) -2-pyridinecarboxylic acid ethyl ester as a yellow solid (289 mg) judged by nmr for be a 2.7: 1 mixture of ethyl esters: methyl; n.m.r d values that include 1.47 (t, 2.9H), 4.04 (s, 0.8H), 4.50 (q, 1.46H), 7.67 (t, 1H), 7.97-7.99 (m, 2H), 8.10-8.16 (m, 1H), 8.29 (d, 1H), 8.43-8.48 (m, 1 H), 8.86-8.87 (m, 1 H); from the ethyl ester of 2-bromo-6-pi r idine -carboxylic acid (1.2 g) in toluene (20 ml), tet rachis (triphenylphosphine) palladium (0) (181 mg), 2M aqueous sodium carbonate ( 3.3 ml), and 3-nitrobenzyl acid (1.0 g) in methanol (5 ml).

Intermediary 26 3'-Hydroxy- [1,1'-biphenyl] -3-carboxylic acid methyl ester To a solution of methyl 3 - (3-methylmethyl) methylbenzoate (1.48 mg) at -78 ° C in anhydrous methylene chloride (16 ml) a solution of boron tribromide in methylene chloride (1.0 M, 16.3 ml) is added dropwise. The mixture is stirred at -78 ° C for 30 minutes, allowed to warm to 0 ° C, and stirred for 2 h. The mixture is quenched by the addition of saturated aqueous sodium bicarbonate (50 ml), and diluted with methylene chloride (50 ml). The The mixture is placed in a separatory funnel, and the organic layer is separated, dried over sodium sulfate, filtered and concentrated to produce the crude product. Purify by chromatography on silica gel (elute with hexanes / ace t to t or ethyl 5: 1) to obtain the title compound (769 mg) as a pale yellow oil. NMR d values including 3.94 (s, 3H), 6.84 (d, 1H), 7.09 (s, 1H), 7.18 (d, 1H), 7.31 (t, 1H), 7.49 (t, 1H), 7.75 (d , 1H), 8.01 (d, 1H), 8.25 (s, 1H).

Intermediate 27 3'-nitro-biphenyl-3- (lH-5-tetrazolo) To a stirred mixture of 3 '-not t- [1, 1'-bi f eni 1] -3 -carbonyl t (800 mg ) and triethyl azide 1 if 1 i (823 mg) in toluene (10 ml) is added dimethyltin oxide (59.3 mg). The reaction is heated at 100 ° C overnight. The mixture is concentrated, diluted with methanol (5 ml) and concentrated again. The mixture is separated between a saturated solution of sodium bicarbonate and ethyl acetate. The layer The organic phase is extracted again with a sodium bicarbonate solution and the combined aqueous layers are acidified with IN hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are then dried over magnesium sulfate, filtered and concentrated to yield a white solid (377 mg). p.f. 271-273 ° C.

Intermediate 2 Methyl ester of 3'-amino [1,1'-bi phenyl] -3-carboxylic acid It is added to a stirred solution of the 3'-nitric acid ester 0- [1, 1'-bi-phenyl] 1] - 3 -carboxylic (4.47 g) in anhydrous tetrahydrofuran (125 ml) under a nitrogen blanket 10% palladium on activated charcoal (860 mg) is added. The reaction is evacuated and placed under a nitrogen atmosphere and stirred overnight. The reaction mixture is filtered through Zeolite and the solvent is removed under reduced pressure to yield a gray oil (4.4 g). The residue is chromatographed on silica gel and eluted with hexane: ace tat or ethyl 3: 1. Concentration of the appropriate fractions gives the title compound as a white solid (3.5 g). n.m.r. d values including 3.83 (s, 2H), 3.93 (s, 3H), 6.70 (d, 1H), 6.93 (d, 1H), 7.00 (d, 1H), 7.25-7.21 (m, 1H), 7.47 ( t, 1H), 7.73 (d, 1H), 7.98 (d, 1H), 8.23 (d, 1H).

They are prepared in a similar manner: Intermediate 29 3 '-amino- [1,1'-biphenyl] -4-carboxylic acid methyl ester as a pale yellow solid (170 mg); Electrorrocy MS (positive ion): (M + H) 228; from the methyl ester of 3 '-nitro- [1,1] -bi f eni 1] -4 -carboxylic acid (196 mg).

Intermediate 30 Methyl 3'-amino- [1,1'-biphenyl] -2-methyl-5-carboxylic acid methyl ester as a white crystalline solid (572 mg); Electrorrocy MS (positive ion): (M + H) 242.5; from 3'-nitro- [1,1'-biphenyl] -2-meth i-5-carboxylic acid methyl ester (605 mg).

Intermediate 31 Methyl ester of 3'-amino- [1,1'-biphenyl] -2-carboxylic acid as a pale yellow solid (910 mg); n.m.r. (DMS0-d6) d values including 3.58 (s, 3H), 5.13 (s, 2H), 6.38 (d, 1H), 6.51 (m, 2H), 7.02 (t, 1H), 7.40 (m, 2H) , 7.58 (m, 2H): from the methyl ester of 3'-nitro- [1,1'-phenyl] -2-carboxylic acid (1.05 g).

Intermediate 32 5- (3-Amino-en-1-yl) -3-pyridinecarboxylic acid ethyl ester as a pale yellow solid (19.9 mg); n.m.r. d values including 1.42 (t, 3H), 4.43 (q, 2H), 6.75 (dd, 1H), 6.90 (t, 1H), 6.98 (d, 1H), 8.43 (t, 1H), 8.95 (d, 1H), 9.16 (d, 1H); from 5- (3-nit-rofyl) -3-pyridinecarboxylic acid ethyl ester (100 mg).

Intermediary 33 Dimethyl ester of 3'-amino- [1,1'-bi phenyl] -2,4 -dicarboxylic acid (458 mg), n.m.r. (DMSO-d6) d values including 3.64 (s, 3H), 3.88 (s, 3H), 5.21 (s, 2H), 6.41 (d, 1H), 6.52 (s, 1H), 6.56 (d, 1H) , 7.06 (t, 1H), 7.54 (d, 1H), 8.10 (d, 1H), 8.17 (s, 1H).

Intermediate 34 Methyl ester of 5- (3-amino-phenyl-1) -3-pyridinecarboxylic acid (187 mg); n.m.r. (DMSO-d6) d values including 3.91 (s, 3H), 5.28 (s, 2H), 6.64 (m, 1H), 6.89 (m, 2H), 7.15 (t, 1H), 8.34 (s, 1H) , 9.02 (s, 2 H); from the methyl ester of 5- (3-ni t rof eni 1) -3-pyridinecarboxylic acid (220 mg).

Intermediate 35 3'-amino- [1,1'-biphenyl] -3-carbonitrile as a yellow oil (229 mg); n.m.r. d values including 3.80 (bs, 2H), 6.72 (dd, 1H), 6.84 (s, 1H), 6.92 (d, 1H), 7.22-7.26 (m, 2H), 7.50 (t, 1H), 7.59 ( d, 1H), 7.76 (d, 1H), 7. 82 (s, 1H); from 3 '-not t ro- [1, 1'-bi f eni 1] -3-carbonyl t-rile (430 mg).

Intermediary 36 5 - (3 - ami nof in i 1) - 4 - pyridinecarboxylic acid ethyl ester To a solution of 5- (3-aminophenyl) -4-pyridinecarboxylic acid ethyl ester in ethyl acetate (20 ml ) tin chloride (II) (1.47 g) is added. The mixture is heated at 80 ° C for 45 minutes, then allowed to cool to room temperature. The mixture is poured into ice and saturated aqueous sodium bicarbonate is added until the mixture reaches a pH of about 7. Ceuta and ethyl acetate are added, and the mixture is stirred for 10 minutes. The mixture is filtered and placed in a separatory funnel. The organic layer is separated, dried over sodium sulfate, filtered and concentrated to yield the crude product. Purify by chromatography on silica gel (hexane: ethyl acetate 4: 1) to obtain the title compound as an orange oil (216 mg). n.m.r. d values that include 1.42 (t, 3H), 4.43 (q, 2H), 6.86 (d, 1H), 7.29 (t, 1H), 7.44 (d, 1H), 7. 51 (s, 1H), 7.78 (d, 1H), 8.26 (s, 1 H); 8.80 (d, 1 HOUR) .

They are similarly prepared: Intermediate 37 Methyl 3'-amino- [1,1'-biphenyl] -3-chloro-4-carboxylic acid methyl ester (788 mg); n.m.r. d values that include 3.93 (s, 3H), 6.72 (d, 1H), 6.88 (s, 1H), 6.96 (d, 1H), 7.25 (m, 1H), 7. 49 (dd, 1H), 7.64 (d, 1H), 7.89 (d, 1H); from 3'-nitro- [1,1'-biphenyl] -3-chloro-4-carboxylic acid methyl ester (1.0 g) and tin (II) chloride (3.9 g).

Intermediary 38 2 - (3-amino-1-en-1) -3-pyridinecarboxylic acid methyl ester (275 mg); n.m.r. (DMSO-d6) d values including 3.65 (s, 3H), 5.19 (s, 2H), 6. 58 (dt, 2H), 6.76 (s, 1H), 7.05 (t, 1H), 7.44 (dd, 1H), 8.02 (d, 1H), 8.73 (d, 1H); from the methyl ester of 2 - (3-nor t ro feni 1) - 3 - pyridinecarboxylic (293 mg) and 10% Pd / C (30 mg).

Intermediate 39 Dimethyl ester of 3'-amino- [1,1'-biphenyl] -3,4 -dicarboxylic acid (680 mg); n.m.r. (DMSO-d6) d values including 3.77 (s, 2H), 3.91 (s, 3H), 3.92 (s, 3H), 6.70 (m, 1H), 6.89 (s, 1H), 6.97 (d, 1H) , 7.21 (d, 1H), 7.69 (m, 1H), 7.79 (d, 1H), 7.85 (m, 1H); from the dimethyl ester of 3'-nitric oxide [1, 1 '-bi f eni 1] - 3, 4 -dicarboxilic acid (0.8 g) and 10% Pd / C (560 mg) in tetrahydrofuran (30 ml ).

Intermediate 40 5 - (3-aminophenyl) -2,3-dihydro-7-benzofurancarboxylic acid methyl ester It is heated at 70 ° C for 16 h 5 - (3-ni t rof eni 1) -2 methyl ester, 3, -dihydro-7-benzo furancarboxi 1 i co (650 mg) and tin chloride (II) (2.3 g) in ethyl acetate (28 ml). The mixture is allowed to cool and poured into ice. The pH is adjusted to 7-8 by the addition of bicarbonate of saturated aqueous sodium, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, treated with charcoal and dried over sodium sulfate. Filtration and removal of the solvent produces the title compound as an oil (470 mg). Electrorrocy MS (positive ion): (M + H) 270.4.

They are similarly prepared: Intermediate 41 Amino- [1,1 '-biphenyl] -3- (lH-5-tretrazolo) as a light brown oil (57 mg); n.m.r. (CD3OD) d values including 6.75 (d, 1H), 7.02-7.07 (m, 2H), 7.20 (t, 1H), 7.54 (t, 1H), 7.69 (d, 1H), 7.96 (d, 1H) , 8.25 (s, 1H); from 3'-nitro- [1,1 '-biphenyl] -3- (lH-5-tetrazolo) (371 mg) and tin (II) chloride (1.57 g).

Intermediary 42 6- (3-amino-phenyl-1) -2-methyl ester • pyridine-carboxylic acid and 3'-ethyl ester 3-aminophenyl) -2-pyridinecarboxylic acid as a brown oil (126 mg) appears to be a 1: 2.5 mixture of the methyl and ethyl esters; Electrorrocio MS (positive ion); (M + H) 229.2 and 243.2; from the methyl ester of 6 - (3-nitrofenyl) - 2-pyridine-carboxylic acid ester and 6 - (3-nitrofenyl) ethyl ester - 2-pyridine ca rboxi 1 i co (280 mg) and tin chloride (II) (1.16 g).

Intermediate 43 3 '- [2- [[(tert-butoxy) carbonyl] amino] ethoxy] - [1,1' -bi-f -1] -3-carboxymethyl methacrylate A mixture of methyl 3-methyl ester '-hydroxy- [1, 1' -bi-phenyl] -3-carboxylic acid (667 mg) and 2-bromo-1 [(tert -but oxycarbonyl) amino] et anus (980 mg) in N, N-dimme ti 1 f ormami da (15 ml) with potassium carbonate (2.0 g). The mixture is stirred at room temperature for 30 minutes, and heated at 50 ° C in an oil bath for 14 hours. Additional bromide (396 mg) is added and the mixture is heated an additional 36 h. The mixture is cooled to room temperature and separated between ethyl acetate hexane and water 1: 1. The organic layer is separated, washed with water, dried over sodium sulfate, sodium, it is filtered and concentrated to produce the crude product. Purify by chromatography on silica gel (elute with hexane / ethyl acetate 5: 1) to obtain the title compound as a colorless oil (826 mg). NMR d values including 1.44 (s, 9H), 3.56 (m, 2H), 3.93 (s, 3H), 4.07-4.11 (m, 2H), 5.01 (s, 1H), 6.89-6.91 (m, 1H) , 7.13 (s, 1H), 7.36 (t, 1H), 7.49 (t, 1H), 7.75 (d, 1 H); 8.01 (d, 1H), 8.24 (s, 1H).

Intermediate 44 3 '- [(2- [[(tert-butoxy) carbonyl] amino] acetylamino)] - [1, 1' -bi f eni 1] - 3-ca rboxi 1 methyl a mixture to a methyl ester mixture of 3'-amino- [1,1'-bifenyl] -3-carboxylic acid (1.14 g) and N- (tert -but-oxycarbonyl-1) glycine (0.879 g) in methylene chloride (20 ml) 1- (3-dimethylaminopropy 1) -3-eti-1-carbodiimide hydrochloride (1.20 g) is added. The mixture is stirred for 3 hours at room temperature, then washed twice with IN aqueous HCl, twice with aqueous sodium bicarbonate. saturated and once with brine. The mixture is dried over sodium sulfate, filtered and concentrated to produce a foam. Purify by chromatography on silica gel and elute with 7: 3 hexane / ethyl acetate to yield 1.6 g of the title compound as a colorless oil. Electrorrocy MS (positive ion): (M + H): 407.0.

Intermediate 45 [(2- [[(tert-butoxy) carbonyl] amino] ethyl) amino] - [1,1 '-biphenyl] -3-carboxymethyl methoxycarbonate is added at 0 ° C to 3' - [(2- [[(tert-butoxy) carbonyl] amino] acetylamino)] - [1,1'-bi-fyl] -3-carboxylic acid methyl ester (1.6 g) a solution of 1.0 M borane in tetrahydrofuran ( 30 ml). The mixture is heated to room temperature and stirred for 3 hours. The mixture is quenched with saturated aqueous sodium bicarbonate and concentrated to leave a dark liquid that separates between ethyl acetate and saturated aqueous sodium bicarbonate. The separated organic layer is washed with brine, dried over sodium sulfate, sodium, it is filtered and concentrated to produce the crude product. Purify by chromatography on silica gel to give the title compound (740 mg). Electrorrocio MS (positive ion): M + Na 393.0 Intermediate 46 3 '- [(2-aminoethyl) amino] - [1,1-biphenyl] -3-methylcarboxylate It is added to met il-3' - [(2- [[(tert-but-oxy)] carbonyl] amino] ethyl) amino] - [1,1 '-biphenyl] -3-carboxylate (730 mg) 4N HCl and dioxane (20 ml) and the mixture is stirred under nitrogen for 16 h. The white mixture is diluted with ether, and the dihydrochloride salt of the title compound is collected as a white solid (565 mg) by suction filtration. A portion of this material (128 mg) is divided between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (30 ml). The combined organic layers are dried over sodium sulfate, filtered and concentrated to yield the title compound (117 mg) as a colorless oil. Electrorrocy MS (positive ion): [M + H) 272.

Intermediate 47 R) - (-) -3- (phenyloxy) -1, 2-epoxypropane (U7924 9-2 It is added to a solution of phenol (336 mg) in anhydrous N, N-dimethyl formamide (16 ml) sodium hydride (60% in mineral oil, 190 mg). The mixture is stirred for 1 hour and (2S) - (+) - glycidyl 3-nor trobenzene sulfonate (1.0 g) in N, N-dimethylformamide (5 ml) is added. The mixture is heated to 60 ° C and stirred for 30 minutes. The reaction is allowed to cool to room temperature, water is added (100 ml) and the mixture is extracted with hexane: acetat or ethyl 2: 1 (40 ml twice). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to provide the crude product. Purify by chromatography on silica gel (elute with hexane: ethyl acetate 10: 1) to give the title compound (474 mg) as a colorless oil. NMR d values including 2.75 (dd, 1H), 2.90 (t, 1H), 3.35 (t, 1H), 3.95 (dd, 1H), 4.20 (dd, 1H), 6.90-6.97 (m, 3H), 7.24 -7.30 (m, 2H).

Intermediate 48 Methyl-3 '- [(2-amino) ethoxy] - [1,1'-biphenyl] -3-carboxylate. The methyl-3 '[2- [[(tert-butoxy) carbonyl] amino] ethoxy] - [1,1'-biphenyl] -3-carboxylate (659 mg) is dissolved in methylene chloride (25 ml) and add acetic acid (2.5 ml). The mixture is stirred at room temperature for 6 hours, additional trifluoroacetic acid (1.0 ml) is added and the mixture is stirred overnight. The mixture is concentrated and divided between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is separated, dried over sodium sulfate, filtered and concentrated to yield the crude product. This residue is partitioned between hexane: ethyl acetate 1: 1 and aqueous HCl IN. The aqueous layer is separated, washed with hexane: acetat or ethyl 1: 1 and made basic by the addition of solid sodium bicarbonate. The mixture is extracted twice with ethyl acetate, and the combined organic extracts are dried over sodium sulfate, filtered and concentrated to yield the title compound (474 mg) as a colorless oil.

Electrorrocio MS (positive ion): (M + H) 272.0 Intermediate 49 (R) -3 '- [2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethoxy] - [1,1'-biphenyl] -3-carboxylic acid methyl ester. A solution of me thi-3 '- [(2-amino) et ox i] - [1,1' -bifinyl] -3-carboxy lat or (284.5 mg) is heated at 70-75 ° C for 20 hours. ) and (R) - (-) - 3-chlorostyrene oxide (124 mg) in nitromethane (4.0 ml). The mixture is concentrated with a rotary evaporator to produce the crude compound. Purify by silica gel chromatography (elute with ethyl acetate followed by 10: 1 ethyl acetate: followed by 3: 1 ethyl acetate: tannol), to yield the title compound (190.6 mg ) as a colorless oil. Electrorrocy MS (positive ion): (M + H) 425.9.

They are prepared similarly: Intermediate 50 (R) -3 '- [[2 - [(2-hydroxy-3-phenoxypropyl) amino] ethyl] amino] - [1, 1' - methyl ester] bifenil] - 3 - ca rboxi 1 i co as a reddish oil (37 mg); Electrorrocio MS (positive ion); (M + H) 421.1; from me ti 1 - 3 '- [(2-amino-thi-1) amino] - [1,1'-bi-f-1] -3-carboxylato (117 mg) and (R) - (-) - 3- (phenyloxy) -1,2-epoxypropane (54 mg).

Intermediate 51 Acid R) -2- (3,5-dichlorophenyl) -2-hydroxyethanoic acid. The title compound is prepared from the corresponding cyanohydrin, which is obtained from 3,5-dichlorobenzaldehyde by a modification of the procedure used by Huuhtranen and Kanerva for the synthesis of optically active aliphatic cyanohydrins. { Tetrahedron asymmetry 1992, 3, 1223). The procedure of Ziegler et al. to convert cyanohydrin to mandelic acid. { Synthesis 1990, 575). Degreased almond milled grain (18.0 g, Sigma) is moistened with an aqueous citrate buffer (45 ml, 0.018M, pH 5.5). After 15 minutes, isopropyl ether (405 ml) is added to the wet solid, followed by 3, 5 -di cl or oben z to ldeh ido (16.07 g) and acetone cyanohydrin (24.90 ml). The mixture is then stirred at 400 rpm in a sealed flask at room temperature for 24 hours. The mixture is filtered, and the reddish milled grain is extracted with ethyl acetate. The extracts are combined with the filtrate, concentrated to a yellow oil, which is dissolved in concentrated hydrochloric acid (27 ml). The solution is stirred at 75 ° C for 4 hours. The resulting thick thick white slurry is cooled, diluted with water (100 ml), and extracted with ether. The ether extracts are back extracted with an aqueous sodium hydroxide solution. The acidification of the basic extracts for a pH of 1 (pH paper) by the dropwise addition of hydrochloric acid that causes an oil that separates out of the phase accuses. The mixture is then extracted with ether. These extracts are dried (magnesium sulfate), and concentrated to yield the title compound as a white crystalline solid (20.88 g). p.f .: 105-106 ° C.

Intermediate 52 (R) -2- (3, 5-dichlorophenyl) -2-hydroxyethanoic acid methyl ester. A solution of (R) -2- (3,5-di-chloromer) acid is stirred at reflux under nitrogen for 16.5 hours. eni 1) -2-t-hydroxy (19.10 g) in methanol (200 ml) containing concentrated sulfuric acid (1 ml). The solution is then concentrated under vacuum, and the resulting oil is dissolved in ethyl acetate (200 ml). This solution is washed with a saturated aqueous sodium bicarbonate solution, followed by a saturated aqueous sodium chloride solution (10 ml). After drying (magnesium sulfate), the ethyl acetate is removed, and the yellow oil is recrystallized from hexane (70 ml) to yield the title compound as a colorless crystalline solid (10.68 g). The mother liquor produces an additional product (3.61 g) under concentration. p.f. : 68-69 ° C.

Intermediary 53 (R) -2- [Tert-Butyl (dimethyl) silyl] oxy-2- (3,5-di chlorofenyl) ethanoate or methyl A solution of (R) -2 - (3) is stirred under nitrogen for 18 hours. , Methyl 5 -di chloro f eni 1) -2-hydroxyethoacetate (10485 g), tert-butyl chloride i limethe ili lo (8.07 g), and imidazole (3.64 g) in N, -dimet i formamide (50 ml). The volatiles are removed under vacuum and the residue is chromatographed on silica gel, eluting with hexane / ethyl acetate (20: 1). The title compound is obtained as a colorless oil (15.05 Found test: c 51.67, H 6.29, Cl 20.19%, C15H22O3CI2SI requires C 51.57, H 6.35, Cl 20.30%.

Intermediate 54 (R) -2- [tert-Butyl (dimethyl) silyl] oxy -2- (3,5-dichlorophenyl) ethanal. Diisobutylaluminium hydride (56.5 ml, 1.5 M in toluene) is added dropwise about 1 hour to cool the solution (-78 ° C) of (R) -2- [tert-butyl (dimethyl) silyl] oxy-2 - (3,5-dichlorophenyl) ethanoate or methyl (14.81 g) in toluene (150 ml) under nitrogen. The resulting discolored solution is stirred at this temperature for 1 hour, before a saturated aqueous solution of Rochelle's salt (70 ml) is added slowly. The resulting mixture is allowed to warm to room temperature, and then diluted with ethyl acetate. The two-phase system is filtered through Ceuta, washed with water and ethyl acetate. The filtrate is separated into its two layers, and the aqueous layer is extracted with ethyl acetate. The extract and the organic layer of the filtrate are combined, washed with a saturated aqueous sodium chloride solution, dried (magnesium sulfate), and concentrated to yield (2 R) -2- [t ert -butyl (dimethyl ) silyl] oxy-2- (3,5-dichlorophenyl) ethanal as a colorless oil (13.36 g). Based on its "A NMR spectrum, the title compound completes 50% ca. of oil.NMR d values include 0.15 (s, 3H), 0.21 (s, 3H), 1.03 (s, 9H), 5.00 (s, 1H), 7.22-7.39 (m, 3H), 9.56 (s, 1H).

Intermediary 55 (R) -2- (Tert-butoxycarbonyl) [2- [tertbutyl (dimethyl) silyl] oxy-2- (3,5-di chlorofeni 1) e t i 1] aminoacetic acid methyl ester. The glycine methyl ester hydrochloride (7.87 g) is added to the solution of (R) -2- [tert-butyl (dimethyl) silyl] oxy-2- (3,5-dichlorophenyl) ethanal crude (13.36 g) in dichloromethane ( 200 ml) under nitrogen. Triethylamine (8.74 ml) is then added, and the reaction mixture is stirred for 30 minutes. Sodium triacetoxyborohydride is added (17.71 g), and the yellow mixture is stirred at room temperature for 22 hours. The reaction mixture is then diluted with a saturated aqueous solution of a Rochelle salt (75 ml). The two layers are separated, and the dark aqueous phase is extracted with dichloromethane (70 ml). The extract is combined with the organic layer, washed with saturated aqueous sodium chloride (75 ml), dried (magnesium sulfate), and concentrated under vacuum to yield a yellow oil (17.10 g). Distert-butyl dicarbonate (10.56 ml) is added to the yellow oil, and the resulting solution is heated at 95 ° C under nitrogen for 1 hour. The The solution is cooled to room temperature, and chromatographed on silica gel, eluting with hexane. A colorless oil (14.221 g) consisting of the desired product and 30% ca is obtained. (R) -2- [tert-Butyl (dimethyl) sili] oxy-2- (3,5-dichlorophenyl) -1-ethanol. In addition to removing the alcohol, the tert-butyl chloride is added to the solution if lilo (2.11 g) and the imidazole (953 mg) of the oil (14.221 g) in acetonitrile (60 ml). The reaction mixture is stirred under nitrogen for 2 hours. The volatiles are then removed under vacuum, and the residue is chromatographed on silica gel, eluting with hexane / ethyl acetate (from 1: 0 to 10: 1). In this way, a sample of the title compound is obtained by containing 4% of (R) -2- [tert-butyl (dimethyl) silyl] oxy -2- (3,5-dichlorophenyl) -l-ethanol (10.25 g) . Low resolution MS (ES +) 514/516 (M + Na).

Intermediate 56 (R) - [(tert-butoxycarbonyl) - [2- (tert-butyl (dimethyl) silanyloxy) -2- (3,5-dichloro-phenylethyl] -amino] acetaldehyde.

Diisobutylaluminum hydride (1.5 M in toluene, 3.9 ml) is added to methyl- (R) -2- (tert-butoxycarbonyl) - [2- (tert-butyl (dimethyl) silyl] oxy) -2- (3, 5) -dichlorophenyl) etl] amino] acetate (1.5 g) in toluene (25 ml) at -78 ° C. The mixture is stirred for 75 minutes, quenched with methanol (4 ml) followed by 15% aqueous sodium potassium tartrate (10 ml). The mixture is filtered through a pad of Ceuta, and the filtrate is placed in a separatory funnel after the addition of ethyl acetate. The organic layer is separated, dried over sodium sulfate, filtered and concentrated to obtain the title compound (1.3 g). nmr d values include -0.13 (d, 3H), 0.02 (d, 3H), 0.88 (d, 9H), 1.42 (d, 9H), 2.9-3.2 (m, 1H), 3.4-3.65 (m, 1H ), 3.75-4.15 (m, 2H), 4.8-5.0 (m, 1H), 7.05-7.35 (m, 3H), 9.50 (d, 1H).

Intermediate 57 Methyl ester of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2 [[(tertbutyl) dimethylsilyl]] oxy] ethyl] [(tert- butoxy) carbonyl] amino] ethyl] amino] - [1,1 '-biphenyl] -3-carboxylic acid. To a stirred solution of the methyl ester of 3'-amino- [1, 1 '-bi f eni 1] - 3 -carboxylic acid (3.0 g) and (R) - [(tert-butoxycarbonyl) - [ 2 - (Tert-butyldimethylsilanyloxy) -2- (3-chlorofenyl) et i] amino] acet aldehyde (8.2 g) in anhydrous dichloromethane (65 ml) is added acetic acid (8 drops). After stirring for 25 minutes, sodium triacetoxyborohydride is added (5.6 g) and the reaction is stirred overnight. The reaction is quenched with saturated aqueous sodium bicarbonate and more dichloromethane is added. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure to produce a white foam. The residue is purified by chromatography on silica gel and eluted with hexane: ethyl acetate 9: 1 to give the title compound as a white foam (5.62 g). Electrorrocy MS (positive ion): (M + H) 640.0.

They prepare similarly Intermediary 58 3 '- Methyl ester - [[2 R- [[2- (3-chlorophenyl) -2R- [[(tertbutyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] aminojpropyl] amino] - [1 , 1'-biphenyl] -2-carboxylic acid as a white foam (580 mg); MS electrorroium (positive ion): (M + Na + Boc) 553; from 3'-amino- [1,1'-biphenyl] -2-carboxylic acid methyl ester (375 mg) and [2R- (tert-butoxycarbonyl) - [2R- (tert-butyldimethylsilanoxy) - 2 - (3-chloropheni 1) et i 1] amino] propione ldehyde (651 mg).

Intermediary 59 3 '- [[2R- [[2- (3-Chlorophenyl) -2R- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] propyl] amino acid methyl ester - [1,1'-biphenyl] -4-carboxylic acid as a white foam (296 mg); Electrorrocy MS (positive ion): (M + H) 653; from [2R- (tert-butoxycarbonyl) - [2R- (tert-but iimdim i ls i lanoxy) -2- (3-chlorophenyl) etl] amino] -propionaldehyde (340 mg) and methyl ester of 3 '-amino- [1,1' -bifinyl] -4-carboxylic acid (168 mg).

Intermediary 60 Dimethyl acid ester 3 '- [[2 R- [[2 - (3-chlorophenyl) -2R- [[(tertbutyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] propyl] amino ] - [1,1'-biphenyl] -2,4-dicarboxylic acid as a yellow foam (339 mg); Electrorrocy MS (positive ion): (M + H) 711; from the dimethyl ester of 3'-amino- [1,1'-biphenyl] -2,4-dicarboxylic acid (456 mg) and [2R- (tert-butoxycarbonyl) - [2R- (tert- but i ldimet i lsi lanoxi) -2- (3-c 1 gold feni 1) et i 1] amino] propione ldehyde (609 mg).

Intermediary 61 5 - [3- [[2R-2 - [[2- (3-Chlorophenyl) -2-2- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] aminojpropyl methyl ester ] amino] phenyl] -3- pyridinecarboxylic acid as a white foam (339 mg); Electrorrocy MS (positive ion): (M + H) 654; from 5- (3-aminofenyl) -3-pyridinecarboxylic acid methyl ester (185 mg) and [2R- (tert-butoxycarbonyl) - [2R- (tert-butyldimethylsilanoxy) -2- (3-chloropheni 1) et il] amino] propionaldehyde (317 mg).

I termediary 62 2 - [3 - [[2 R - [[2- (3-Chlorophenyl) -2R- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] methyl ester propyl] amino] -phenyl] -3-pyridinecarboxylic acid as a white foam (339 mg); Electrorrocy MS (positive ion): (M + H) 654; from 2- (3-aminophenyl) -3-pyridinecarboxylic acid methyl ester (273 mg) and. {2R- (tert-butoxycarbonyl) - [2R- (tert-butyldimethylsilanoxy) -2- ( 3-chlorophenyl) ethyl] amino.}. Propionaldehyde (504 mg).

Intermediate 63 (R) -3 '- [[2- [[2- (3-chlorophenyl) -2- [[(tert' butyl) dimethylsilyl] oxy] ethyl] [(tert-butyloxy) carbonyl] dimethyl ester amino] ethyl] amino] - [1,1'-biphenyl] -2, -dicarboxylic acid as a foam (1.8 g); n.m.r d values include -0.14 (s, 3H), -0.01 (s, 3H), 0.85 (s, 9H), 1.43 (s, 9H), 3.94 (s, 3H), 7.41 (d, 1H); from the dimethyl ester of [3'-aminophenyl] -2,4-dicarboxylic acid (1.38 mg) and (R) - (tert-butoxycarbonyl) - [2- (tert-butyldimethylsilanoxy) -2- (3-chlorophenyl) ethyl] amino] -acetaldehyde (605 mg).

Intermediate 64 (R) -3 '- [[2 - [[2- (3-Chlorophenyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] methyl ester ethyl] amino] - [1,1'-biphenyl] -3-chloro-4-carboxylic acid as a foam (884 mg); n.m.r d values include -0.13 (s, 3H), 0.01 (s, 3H), 0.86 (s, 9H), 1.47 (s, 9H), 3.03-3.65 (m, 6H), 3.92 (s, 3H), 7.88 (d, 1 H); from the methyl ester of 3 '-amino- [1,1' -bi f eni 1] - '3-chloro-4-carboxylic acid (500 mg) and (R) - (tert-butoxycarbonyl) - [2- (tert-butyldimethylsilanoxy) -2- (3-chlorophenyl) ethyl] amino] -acetaldehyde (1.0 g).

Intermediate 65 Methyl ester of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] ethyl] amino] - [1,1'-biphenyl] -2-methyl-5-carboxylic acid as a white foam (509 mg); Electrorocio MS (positive ion): (M + H) 653.3; of 3'-amino- [1,1'- bi phenyl] -2-met i 1-5-carboxylic acid methyl ester (500 mg) y. { 2R- (tert-butoxycarbonyl) - [2- (tert-butyldimethylsilanoxy) -2- (3-chlorophenyl) ethyl] amino} - acetaldehyde (1.3 g).

Intermediary 66 Methyl ester of (R) -5- [3- [[2 - [[2- (3-chlorophenyl) -2- [[(tert- butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] ethyl] amino] -phenyl] -2,3-dihydro-7-benzofurancarboxylic acid as a foam (691 mg); TLC Rf (hexane / ethyl acetate 4: 1) = 0.14; of 5- (3-aminophenyl) -2,3-dihydro-7-benzofur ancarboxylic acid methyl ester (500 mg) and (R) - [(tert-butoxycarbonyl) - [2- (tert-butyldimethylsilanoxy) - 2- (3-chlorophenyl) ethyl] amino] -acetaldehyde (1.3 g).

Intermediate 67 (R) - 5 - [[2 - [[2 - (3-chlorophenyl) -2- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino acid ethyl ester ] ethyl] amino] - [phenyl] -3-pyridinecarboxylic acid as a yellow foam (372 mg); Electroroxy MS (positive ion): (M + H): 654.4; of 5 - (3-amino f eni 1) - 3-pyridinecarboxylic acid ethyl ester (0.19 g) and (2R- (tert-butoxycarbonyl) - [2R- (tert-butyldimethylsilanoxy) -2- (3-chlorophenyl) ethyl ] amino] -acetaldehyde (0.6 g).

Intermediate 68 (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino dimethyl ester] ethyl] amino] - [1,1'-biphenyl] -3,4 -dicarboxylic acid as a white foam (1.3 g); Electroroxy MS (positive ion): (M + H): 697.6; of 3 '-amino [1,1'-bi-phenyl] -3,4 -dicarboxylic acid dimethyl ester (580 mg) and (R) - [(tert-butoxycarbonyl) - [2- (tert-butyldimethylsilanoxy) -2 - (3-chloropheni 1) e ti 1] amino] -acet aldehyde (1.5 g).

Intermediate 69 (R) -3 '- [[2 - [[2- (3,5-dichlorophenyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] methyl ester amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid as a white foam (1.1 g); nmr d values include -0.12 (s, 3H), -0.01 (s, 3H), 0.86 (s, 9H), 1.45 (s, 9H), 3.92 (s, 3H), 7.47 (t, 1H), 7.98 (d, 1H), 8.21 (s, 1 H); from the 3'-amino [1,1'-biphenyl] -3-carboxylic acid methyl ester (443 mg) and (R) - [(tert- butoxycarbonyl) - [2- (tert-butyl-dimethylsilanyloxy) -2- (3,5-dichlorophenyl) ethyl] amino] -acetaldehyde (1.3 mg).

Intermediate 70 (R) - 2 - [3 - [[2 - [[2- (3-chlorophenyl) -2- [[tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butyloxy) carbonyl] amino acid ethyl ester ] ethyl] amino] - [phenyl] -pi r idine-carboxyl ico as a yellow foam (239 mg); nmr d values include -0.12 (s, 3H), -0.01 (s, 3H), 0.86 (s, 9H), 1.45 (s, 9H), 3.92 (s, 3H), 7.47 (t, 1H), 7.98 (d, 1H), 8.21 (s, 1H); from the 5- (3-amino-f in i 1) -4-pyridinecarboxylic acid ethyl ester (216 mg) and (R) - [(tert-butoxycarbonyl) - [2- (tert-butyl-dimethyl-silanyloxy) -2- (3-chlorophenyl) ethyl] amino] -acetaldehyde (640 mg).

Intermediate 71 (R) -3 '- [[2- [[2- (3-chlorophenyl) -2- [[(tertbutyl) dimethylsilyl] oxy] ethyl] [(tert- butoxy) carbonyl] amino] ethyl] amino] - [1,1 '-biphenyl] -3-carbonitrile as a white foam (637 mg); Electrorocio MS (positive ion): 605.7; of 3'-amino [1,1'-phenyl] -3-carbonitrile (229 mg) and (R) - [(tert-butoxycarbonyl) - [2- (tert-butyldimethylsilanoxy) -2- (3-chlorophenyl) ) ethyl] amino] -acetaldehyde (753 mg) Intermediate 72 (R) -6- [[2 - [[2- (3-Chlorophenyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] ethyl methyl ester ] amino] - [phenyl] -2-pyridinecarboxylic acid ethyl ester (R) -6- [[2- [[2- (3-chlorophenyl) -2- [[(tert-butyl) dimethylsilyl] oxy]] ethyl] [(tert-butoxy) carbonyl] amino] ethyl] amino] - [phenyl] -2-pyridinecarboxylic acid as a yellow oil (263 mg) as a 1: 2.5 mixture of the methyl and ethyl esters; Electrorocio MS (positive ion): (M + H + BOC) 539.9 and 553.9; of methyl ester of the acid 6- (3-amino f in i 1) - 2-pi ri dina-ca rboxi 1 i co, ethyl ester of 6- (3-aminophenyl) -2-pyridinecarboxylic acid (126 mg) and (R) - [(tert-butoxycarbonyl) - [2- (tert-butyldimethylsilanyloxy) -2- (3-chlorofenyl) ethyl] amino] -acet-aldehyde (490 mg).

Intermediate 73 (R) -3- [[2- [[2- (3-chlorophenyl) -2- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] ethyl] amino ] - [1, 1 '-biphenyl] -3 - (1H-5-1 et ra zolo). (A) to a stirred solution of (R) - [(tert-butoxycarbonyl) - [2- (tert-butyldimethylsilanoxy) -2- (3-chlorophenyl) ethyl] amino] -acetaldehyde (134 mg), and 3 '- amino- [[1,1'-biphenyl] -3- [lH-5-tetrazolo] (50 mg) in anhydrous methanol (35 ml) is added acetic acid (45.5 ml). It is then stirred for 10 minutes and sodium cyanobryhydride (33 mg) is added and the reaction is stirred for 64 h. It tends to be divided between Rochelle salt and ethyl acetate. The aqueous layer is extracted again with ethyl acetate. The organic layers are combined and dried with anhydrous sodium sulfate. Intermediate 74 is obtained as a white film (52 mg) - then chromatographed on silica gel (gold form: methanol: ammonium hydroxide 6: 1: 0.1); MS electrorrocio (positive ion): (M + H) 650.1. (B) to a stirred mixture of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] ethyl] amino] -1, 1'-biphenyl] -3-carbonitrile (350 mg) and azide of tr ine 1 if 1 i (134 mg) in toluene (10 ml) is added dimethyltin oxide ( 9.5 mg). The reaction is heated to 100 ° C overnight. Methanol (5 ml) is added, the mixture is transferred to another flask and concentrated. The mixture is divided between a saturated solution of sodium bicarbonate and ethyl acetate. The organic layer is extracted again with a solution of sodium bicarbonate and the combined organic layers are acidified with 3N hydrochloric acid, extracted with ethyl acetate and the combined organic layers are dried with magnesium sulfate, filtered and concentrated produce the raw product. Chromatography is performed with silica gel (gold formaldehyde: meth: ammonium oxide hydro 6: 1: 0.1) to yield the title compound as a light orange foam (117 mg). Electrorocio MS (negative ion): (M + BOC-H) 547.1; Electrorocio MS (positive ion): (M-BOC + H): 549.2.

E j em 1 Acid methyl ester dihydrochloride (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxy-1-yl. To a solution of (R) -3 '- [[2- [[2- (3-chlorophenyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] methyl ester] amino] ethyl] amino] - [1,1 '-biphenyl] -3-carboxylic acid (275 mg) in 4N hydrochloric acid in dioxane (10 ml) is stirred for 3 days. Diethyl ether is added and the reaction is stirred for 20 minutes. The title compound is collected by suction filtration as a white solid (210 mg); C24H25C11N203: MH + calculated 425.1632, found: 425.1635? 0.3 mmu; N.m.r. (CD3OD) d including 3.19-3.13 (m, 1H), 3.36-3.30 (m, 3H), 3.63 (t, 2H), 3.92 (s, 3H), 4.99 (dd, 1H), 6.87 (d, 1H) ), 7.10 (m 2H), 7.37-7.30 (m, 4H), 7.47 (s, 1H), 7.54 (t, 1H), 7.84 (d, 1H), 7.98 (d, 1H), 8.22 (s, 1H) ).

They are prepared in a similar manner: E xample 2 Di orhydrate of (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] dimethyl ester] - [1,1'-biphenyl] -2,4 -dicarboxylic acid as a white solid (478 mg); C26H27C11N205: MH + calculated 483.1687, found 483.1689? 0.2mmu; Found assay: C, 55.95; H 5.26; N 4.98%; C26H27Cl1N2O5.2HC1 requires C 56.18; H 5.26; N 5.0%; From the dimethyl ester of (R) -3 '- [[2- [[2- (3-chlorophenyl) -2 - [[(tert-butyl) imethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] ] amino] ethyl] amino] - [1,1'-biphenyl] -2,4 -dicarboxylic (508 mg) in 4N hydrochloric acid in dioxane (10 ml).

. E xemplo 3 Di Acid methyl ester hydrochloride (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -2-methyl-5-carboxylic acid as a white solid (370 mg); Electroroxy MS (positive ion): (M + H) 439.3; n.m.r. (CD3OD) d values including 2.29 (s, 3H), 3.33 (t, 2H), 3.57 (t, 2H), 3.87 (s, 3H), 4.97 (dd, 1H), 6.72 (m, 2H), 6.81 (d, 1H), 7.26-7.37 (m, 5H), 7.46 (s, 1H), 7.80 (s, 1H), 7.86 (d, 1H); from (R) -3 '- [[2- [[2- (3-chlorofinyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] methyl ester] amino] ethyl] amino] - [1,1'-biphenyl] -2-met i -5-carboxyl ico (508 mg) in 4N hydrochloric acid in dioxane (10 ml). Example 4 Dichlorohydrate of the acid dimethyl ester (R) -3 '- [[2- [[2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3,4-dicarboxylic acid as a white solid (743 mg); C26H27Cl? N205: MH + calculated 483.1687, found 483.1682? -0.5 mmu; Found test: C, 55.03; H 5.36; N 5.04%; C 26 H 27 Cl 1 N 2 O 5 O .64 H 20 requires C 55.04; H 5.38; N 4.9%; From the dimethyl ester of (R) -3 '- [[2- [[2- (3-chlorophenyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] ] amino] ethyl] amino] - [1,1 '-biphenyl] -3,4 -dicarboxylic acid (1.1 g) in 4N hydrochloric acid in dioxane (10 ml).

E j empl o 5 Dichlorohydrate of the acid methyl ester (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-chloro-4-carboxylic acid as a white solid (617 mg); C 24 H 24 Cl 2 N 2? 3: MH + calculated 459.1242, found 459. 1235? -0.7mmu; Found test: C, 54.08; H 4.90; N 5.13%; C24H24C12N203.2HC1 requires C 54.15; H 4.92; N 5.26%; from (R) -3 '- [[2- [[2- (3-chlorophenyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino acid methyl ester ] ethyl] amino] - [1,1'-biphenyl] -3-chloro-4-carboxylic acid (874 mg) in 4N hydrochloric acid in dioxane (10 ml).

Example 6 (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1' -biphenyl] -3- ( lH-5-tetrazolo) as a white solid (18.6 mg); C23H23 60XC11: MH + calculated 435.1700, found 435.1681 d 1.9 mmu; nmr (CD3OD) d values including 3.11-3.19 (m, lh), 3.37 (t, 2h), 3.64 (t, 2h), 4.99 (dd, lh), 6.87 (d, lh), 7.14-7.16 (m , 2h), 7.32-7.34 (m, 4h), 7.46 (s, lh), 7.64 (t, lh), 7.83 (d, lh), 7.96 (d, lh), 8.30 (s, lh), starting from (r) -3 '- [[2 - [[2 - (3-cl gold f in i 1) - 2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] ethyl] amino] - [1,1 '-biphenyl] -3- (1 h-5-1 et ra zolo) (52 mg) in 4N hydrochloric acid in dioxane (10 ml).

Example 7 Di (H) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carbonitrile hydrochloride as a white solid (105 mg); C23H22N3O1CI1: MH + calculated 392.1530, found 392. 1530? 0.1 mmu; Found assay: C, 59.17; H 5.19; N 8.93%; C23H23 3O1Cl1 2HC1 requires C 59.43; H 5.20; N 9. 04%; p. f. 191-206 ° C, from (R) -3 '- [[2 - [[2 - (3-chloro-phenyl-1) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [( tert-butoxy) carbonyl] amino] ethyl] amino] - [1,1 '-biphenyl] -3-carbonityl (173 mg) in 4N hydrochloric acid in dioxane (10 ml).

E j ustric 8 Acid methyl ester dihydrochloride (R) -3 '- [[2- [[2- (3,5-Dichlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid. Methyl ester of (R) -3 '- [[2 - [[2- (3,5-dichlorophenyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] ] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid (1.0 g) is dissolved in 4N HCl in dioxane (10 ml), and stirred for 16 hours. Ether is added and the resulting white solid is collected to yield 704 mg of a pink solid. A portion of this material (150 mg) is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer is separated and concentrated to produce a residue which is treated with IN aqueous HCl in ether. Concentrate, dissolve in methanol / water and the lipolization yield the title compound (82 mg.sup.9 as a solid) C 24 H 24 C 12 N 203: MH + calculated 459.1242, found 459.1224? -1.8 mmu; n.m.r. (DMS0-d6) d values including 3.06-3.30 (m, 4H), 3.85 (s, 3H), 5.01-5.04 (m, 1H), 6.71 (d, 1H), 6.91 (m, 2H), 7.22 ( t, 1H), 7.42 (d, 2H), 7.56 (m, 2H), 7.89 (m, 2H), 8.10 (s, 1H).

E j plic 9 Acid (R) -3 '- [[2- [[2- (3,5-dichlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1' -biphenyl] -3 -carboxi lico. A crude sample of (R) -3 '- [[2 - [[2- (3,5-dichlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1] methyl ester hydrochloride., 1 '-bi-phenyl-1] -3-carboxy-1-yl (for example 8.557 mg), treated with lithium hydroxide monohydrate (220 mg) in methanol / water 3: 1 (28 ml) and stirred for 1 day. Additional monohydrate lithium hydroxide (22 mg) is added and the mixture is stirred overnight. The mixture is treated with 0.5 N aqueous HCl under about pH 6, and the resulting solid (400 mg) is collected by suction filtration. Chromatography is performed with silica gel (eluted with chloroform / methane / ammonium hydroxide 6: 2: 0.1) to produce a solid which is crushed with hexanes. This material is treated with IN aqueous HCl, and the solid is washed by stirring with ethyl acetate. The solid was dried to yield the title compound (78.6 mg). p.f. 197-201 ° C; C23H22 I2N2O3: MH + calculated 445.1086, found 445. 1072? -1.4 mmu; E xample 10 Acid (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1' -biphenyl] - 3 -ca rboxi lico To a solution of (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-methyl ester Carboxylic (4.12 g) in methanol (60 ml) is added to a solution of monohydrate lithium hydroxide (2.08 g) in water (20 ml). The mixture is stirred for 16 hours, and IN hydrochloric acid is added until the mixture is neutral. The mixture is decanted and the residue is purified by flash silica gel chromatography on elution with chloroform / methanol / ammonium hydroxide 6: 2: 0. l) to produce a viscous oil. Triturate with ether and wash with ether to give the title compound as a white solid (2.22 g). C23H23Cl? 2? 3: MH + calculated 411.1475, found 411.1495? -2.0 mmu; Found test: C 65.90; H 5.72; 6.70%; C23H23Cl1N2O3. 0.46 H 0 requires C 65.90; H 5.75; N 6.68%.

They are prepared in a similar manner: Example 11 2-Methyl ester of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1 , 1 '-biphenyl] -2,4-dicarboxylic. The product is prepared from (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1, 1'-b] dimethyl ester hydrochloride. phenyl] -2,4 -dicarboxylic acid (406 mg) and lithium hydroxide monohydrate (262 mg) in methanol-water 3: 1 (20 ml). Chromatograph with silica gel and elute with oroform: me tanol: ammonium hydroxide 6: 2: 0.1 to yield the title compound (35 mg) as a white solid. C25H25Cl? N205: MH + calculated 469.1530, found 469.1522? -0.8 mmu; Found test: C 63.93; H 5.36; N 5.91%; C25H25Cl1N2O5. requires C 64.03; H 5.37; N 5.97%.

E xample 12 Acid (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -2,4 - dicarboxylic. The relevant fractions of the elution are collected from the silica gel column used to produce the Example to produce the title compound (188 mg) as a white solid. C24H23Cl? N2? 5: MH + calc. 455.1374, found 455. 1377? + 0.3 mmu; n.m.r. (CD3OD) d values including 3.44-3.47 (t, 2H), 5.01 (m, 1H), 6.61 (d, 1H), 6.86 (d, 1H), 6.96 (s, 1H). 7.28-7.47 (m, 4H), 7.46 (s, 1H), 7.91 (dd, 1H), 8.11 (d, 1H).

E xemployment 13 Acid (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -2-methyl-5- carboxylic as a white solid (47 mg); C 24 H 25 Cl 1 N 2 O 5: MH + calculated 425.1632, found 425.1638? 0.6 mmu; n.m.r. (DMSO-de) d values including 2.24 (s, 3H), 4.64 (m, 1H), 5.65 (bs, 1H), 6.43-6.45 (m, 2H), 6.54 (d, 1H), 7.10 (t, 1H), 7.67 (s, 1H), 7.74 (d, 1 H); of (R) -3 '- [[2 - [[2 - (3-C lor of en i 1) -2-hydroxyethyl] amino] ethyl] amino] - [1, 1' -] methyl ester dihydrochloride biphenyl] -2-methyl-5-carboxylic acid (300 mg) and lithium hydroxide monohydrate (106 mg).

E xample 14 Acid R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1' -biphenyl] -3-chloro- 4 -carboxylic acid as a yellow solid (205.3 mg); C 23 H 22 Cl 2 N 2 O: MH + calc. 445.1086, found 445.1071? -1.5 mmu; n.m.r. (CD3OD) d values including 3.10-3.24 (m, 1H), 3.56 (t, 2H), 5.00 (dd, 1H), 4.97 (d, 1H), 6.69 (d, 1H), 6.90-6.92 (m, 2H), 7.20 (t, 1H), 7.22 (t, 3H), 7.29-7.37 (m, 3H), 7.42-7.50 (m, 3H), 7.50 (d, 1 H); of (R) -3 '- [[2 - [[2 - (3-cl or of eni-1) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] methyl ester. ] - 3-chloro-4-carboxylic acid (500 mg) and monohydrate lithium hydroxide (158 mg).

E xample 15 Acid (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3,4 - Dicarboxylic acid as a yellow solid (205 mg); C 24 H 23 CN 2 O 5: MH + calculated 455.1374, found 455.1390? +1.6 mmu; n.m.r. (CD3OD) d values including 2.97-3.00 (m, 1H), 3.43-3.45 (m, 2H), 4.97 (dd, 1H), 6.69 (d, 1H), 6.97-6.99 (m, 2H), 7.20- 7.31 (m, 4H), 7.42 (s, 1H), 7.73 (d, 1H), 8.19 (d, 1H), 8.37 (s, 1H); of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3 dimethyl ester, dihydrochloride, 4- dicarboxylic (500 mg) and monohydrate lithium hydroxide (303 mg).

E j plic 16 Acid (R) -3 '- [[2- [[2-hydroxy) -3-phenoxypropyl) amino] ethyl] amino] - [1,1' -biphenyl] -3-dicarboxylic acid as a yellow solid (23.2 mg); C24H26N2O: MH + calculated 407.1971, found 407. 1966? +0.5 mmu; NMR (CD3OD) d values including 3.14-3.20 (m, 1H), 3.54 (t, 2H), 3.95-4.04 (m, 2H), 4.23-4.27 (m, 1H), 6.67 (d, 1H), 7.38 (t, 1H), 7.62 (d, 1H), 7. 65 (d, 1H), 7.88 (d, 1H), 8.19 (s, 1H); of (R) -3 '- [[2 - [[(2-Hydr-oxy-3-phenoxypropyl) amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid methyl ester (37 mg) ) and lithium hydroxide monohydrate (20 mg) in methanol: water 2: 1 (1 ml).

E xample 17 Acid R) -3 '- [[2- [2- (3-chlorofenyl) -2-hydroxyethyl] amino] ethoxy] - [1,1'-biphenyl] -3-carboxylic acid as a white solid (113.0 mg); C23H22C1N04: MH + calculated 412.1316, found 412.1308? +0.8 mmu; NMR (CD3OD) d values including 3.09-3.15 (m, 1H), 3.45 (t, 2H), 4.33 (t, 2H), 4.99 (dd, H), 5.01 (s, 1H), 6.96 (d, 1H) ), 7.47 (s, 1H), 7.65 (d, 1H), 7.92 (d, 1H), 8.20 (s, 1H); of (R) -3 '- [[2 - [[2- (3-chloro f in i 1) -2-hydroxyethyl] amino] ethoxy] - [1,1'-biphenyl] -3- methyl ester carboxylic (190.6 mg) and monohydrate lithium hydroxide (108 mg) in methanol: water 3: 1 (12 ml). E xample 18 3 '- [[2R- [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] - [1,1'-biphenyl] -4-carboxylic acid. A mixture of 3'- [[2R- [[2- (3-chlorophenyl) -2R- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] propyl] amino acid methyl ester ] - [1,1'-biphenyl] -4-carboxylic acid (289 mg) in 4N hydrochloric acid 1,4-dioxane (4 ml) is stirred for 1.5 hours. The mixture is diluted with diethyl ether and stirred for 20 minutes to produce a viscous residue. The solvent is decanted from the residue and the The residue is dried under vacuum. This material is dissolved in methanol-raragua 3: 1 (10 ml), treated with lithium hydroxide monohydrate (120 mg) and stirred overnight. The mixture is concentrated under reduced pressure and chromatographed on silica and eluted with me tanol: dichloromethane: 88% ammonium hydroxide (15: 85: 1.5) to give the title compound as a white solid (31 mg). Electroroxy MS (positive ion): (M + H) 425; HPLC (C18): 98.35% purity, 12.7 minutes retention by using 0.1% strength acid with 0.1% acetonitrile-10% -100% water.

Examples 19-25 are prepared in a similar manner as Example 18.

Example 19 3 '- [[2R- [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] - [1,1'-biphenyl] -2-carboxylic acid as a white solid ( 238 mg); Electrorocio MS (positive ion: (M + H) 425 HPLC (C18): 95.5% purity, 11.8 minutes of retention time when using a mobile phase of gradient of trifluoroacetic acid i co 0.1% with acetonit rilo-agua 30-80% with detection by absorbance at 254 nM: 3'- methyl ester - [[2R- [[2- (3-chlorophenyl) - [ [2R- [[2- (3-chlorophenyl) -2R- [[tert-butyl) dimethylsilyl] oxy] ethyl] [tert-butoxy) carbonyl] amino] propyl] amino] - [1,1 '-bifinyl] -2 Carboxylic acid (575 mg), 4N hydrochloric acid in 1,4-dioxane (5 ml) and monohydric acid (0.1 mg) in lithium oxide (185 mg) in methanol: water 3: 1 (10 ml).

E xample 20 3 '- [[(2R - [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] - [1, 1'-biphenyl] 2,4-dicarboxylic acid as a yellow solid (302 mg); MS electrorocio (positive ion): (M + H) 469 HPLC (C18), 94.2% purity, 8.71 minutes retention time when using a mobile gradient phase of 0.1% trifluoroacetic acid with ace t oni tri lo-agua 30-80% with detection by absorbance at 254 nM, of dimethyl ester of 3 '- [[(2R- [[2- (3-chlorophenyl) -2R- [[(tert- butyl) dimethylsisl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] propyl] amino] - [1, 1'-bi f eni 1] -2,4-dicarboxylic acid (655 mg), hydrochloric acid 4N in 1,4-dioxane (5 ml) and monohydrate lithium hydroxide (256 mg) in methanol-water 3: 1 (4 ml).

Example 21 Acid 5- [3- [[2R- [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] phenyl] -3-pyridinecarboxylic acid as a yellow solid (11 mg); Electrorocio MS (positive ion): (M + H) 426 HPLC (C18), 94.0% purity, 6.30 minutes retention time when using a gradient mobile phase of 0.1% trifluoroacetic acid with ace t oni tri-water 30-80% with detection by absorbance at 254 nM; 5- [3- [[2R- [[2- (3-chlorophenyl) -2R- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] propyl] amino acid methyl ester ] phenyl] -3-pyridinecarboxylic acid (292 mg), 4N hydrochloric acid in 1,4-dioxane (5 ml) and lithium hydroxide monohydrate (65 mg) in 3: 1 t-hydrohydrofuran-3-water (3 ml).

E xample 22 Acid 2- [3 - [[2R- [[2 - (3-c 1-oropheni-1) -2R-hydroxyethyl] ammonium] propyl] amino] phenyl] -3-pyridinecarboxylic acid as a yellow solid (268 mg ); Electrorocio MS (positive ion): (M + H) 426 HPLC (C18), 95.5% purity, 4.79 minutes retention time when using a gradient mobile phase of 0.1% trifluoroacetic acid with ace t oni tri-water 30-80% with detection by absorbance at 254 nM; of 2 - [3 - [[2 R - [[2- (3-chlorophenyl) -2R- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] propyl] methyl ester] amino] phenyl] -3-pyridinecarboxylic acid (420 mg), 4N hydrochloric acid in 1,4-dioxane (4 ml) and lithium hydroxide monohydrate (295 mg) in 3-hydroquinol-water tetrahydrofuran (3 ml).

Acid 23 Acid R) -5- [3 R- [[2- (3-chlorofenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -2,3-dihydro-7-benzofurancarboxylic acid as a yellow solid (197 mg); C25H25Cl? N204: MH + calc. 453.1581, found 453. 1569? -1.2 mmu; Test found C, 61.04, H 5.37, N 5.60; C25H25CI1N2O .0.67LIC1.0.59H20 requires C 61.04, H 5.36, N 5.69; of (R) -5 - [3- [[2- [[2- (3-chlorophenyl) -2- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino acid methyl ester ] ethyl] amino] phenyl] -2,3-dihydro-7-benzofurancarboxylic acid (691 mg), 4N hydrochloric acid in 1,4-dioxane (10 ml) and monohydrate lithium hydroxide (170 mg) in tetrahydrofuran-water 3: 1 (20 ml).

Example 24: Acid R) -5- [3- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -3-pyridinecarboxylic acid as a yellow solid (115 mg C22H2-AI1N3O3: MH + calculated 412.1428, found 412.1425? -0.3 mmu; nmr (CD3OD) d values including 3.11-3.29 (m, 1H), 3.58 (t, 2H), 4.97 (dd, 1H), 6.76 (d, 1H), 6.97 (s, 1H), 6.99 (d, 1H) ), 7.26-7.35 (m, 4H), 7.46 (s, 1H), 8.51 (s, 1H), 8.76 (s, 1H), 9.00 (s, 1H); of (R) -5- [3- [[2 - [[2- (3-chlorophenyl) -2- [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino acid methyl ester ] ethyl] amino] phenyl] -3-pyridinecarboxylic acid (251 mg), 4N hydrochloric acid in 1,4-dioxane (10 ml) and monohydrate lithium hydroxide (96 mg) in t et rahydr or fur ano-water 3 : 1 (20 ml).

E j plic 25 Acid (R) -2- [3- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -3-pyridinecarboxylic acid as a solid yellow (52 mg); Electrorrocy MS (positive ion): (M + H) 412.1; nmr (CD3OD) d values including 3.11-3.17 (m, 1H), 3.58 (t, 2H), 4.96 (dd, 1H), 7.46 (s, 1H), 7.75 (d, 1H), 8.21 (s, 1H) ), 8.59 (d, 1H); of (R) -3 '- [3 - [[2 - [[2- (3-chlorophenyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] ethyl ester] amino] ethyl] amino] - [phenyl] -4-pyridinecarboxylic acid (239 mg), 4N hydrochloric acid in 1,4-dioxane (10 ml) and monohydrate lithium hydroxide (55 mg) in tet rahydro furan-water 3: 1 (15.5 ml).

E xample 26 Acid (R) -6- [3- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -2-pyridinecarboxylic acid as a yellow solid (30 mg); C22H22N3O3CI1: MH + calculated 412.1428, found 412.1436? +0.9 mmu; nmr (CD3OD) d values including 3.24-3.08 (m, 2H), 3.61 (t, 2H), 5.01 (dd, 1H), 6.72 (d, 1H), 7.44 (s, 1H), 7.65 (s, 1H) ), 7.96-7.86 (m, 3 H); of a 2.5: 1 mixture of (R) -6- [3- [[2- [[2- (3-chlorophenyl) -2 - [[(tert-butyl) dimethylsilyl] oxy] ethyl] [(tert) methyl ester] -butoxy) carbonyl] amino] ethyl] amino] phenyl] -2-pyridinecarboxylic acid ester and (R) -6- [3- [[2- [[2- (3-chlorophenyl) -2- [[( tert-butyl) dimethylsilyl] oxy] ethyl] [(tert-butoxy) carbonyl] amino] ethyl] amino] phenyl] -2-pyridinecarboxylic acid (263 mg), 4N hydrochloric acid in dioxane (10 ml) and monohydrate lithium hydroxide (65 mg ) methanolragua (40 ml). The intermediate ester (170 mg) is isolated by column chromatography (eluted with chloroform: methanol: ammonium hydroxide 12: 1: 0.1).

Tablet Compositions The following compositions A and B can be prepared by the wet granulation of ingredients (a) to (c) and (a) to (d) with a povidone solution, followed by the addition of magnesium stearate and the compression.

Composition A Mg / tablet Mg / tablet Active ingredient 250 250 Lactose B. P. 210 26 (c) Glycolate starch 20 12 sodium Povidone B. P. 15 9 (e) Stearate of 5 3 Magnesium 10 500 300 Composition B Mg / tablet Mg / tablet (a) Active ingredient 250 250 (b) Lactose 150 150 (c) Avicel PH 101 60 26 (d) Glycolate starch 20 12 sodium (e Povidone B.P. 15 9 (f) Stearate 5 3 magne s i or 500 300 Compo s i c ion C Mg / tablet Active ingredient 100 Lactose 200 Starch 50 Povidone 5 Magnesium stearate 4 359 The following compositions D and E can be prepared by direct compression of the mixed ingredients. The lactose used in composition E is of the direct compression type.

Composition D Mg / tablet Active ingredient 250 Magnesium stearate Pregelatinized starch 146 NF15 400 Composition E Mg / t ablet a Active ingredient 250 Magnesium stearate 5 Lactose 145 Avi ce 1 100 500 Composition (controlled liberated composition) Mg / tablet (a) Active ingredient 500 (b) Hydroxypropylmethylcellulose 112 (Metocel K4M Premium c) Lactose B. P 53 Povidone B. P. C 28 (e) Magnesium stearate 7 700 The composition can be prepared by wet granulation of the ingredients (a) to (c) with a povidone solution, followed by the addition of magnesium stearate and compression.

Composition G (Coated enteral tablet) Enteric coated tablets of composition C can be prepared by coating the tablets with 25 mg / tablet of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate or phthalate, cellulose phthalate, hydroxypropyl lmet i lo-, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragite L). Except for Eudragite L, they may also include 10% (by weight of the amount of polymer used) of a plasticizer to prevent the membrane from breaking during application or during storage. The most suitable types include diethyl phthalate, tributyl citrate, and triacetin.

Compo s i tion H controlled release tablet Enteric coated) Enteric coated tablets of composition F can be prepared by coating the tablets with 50 mg / tablet of an enteric polymer such as phthalate cellulose acetate, phthalate of polyvinylacetate, cellulose phthalate, hydroxypropylmethyl-, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragite L). Except for Eudragite L, these polymers may also include 10% (by weight of the amount of polymer used) of a plasticizer to prevent the membrane from breaking during application or during storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

Capsules composition Composition A The capsules can be prepared by mixing the ingredients of composition D above and filling the two-part hard gelatin capsules with the resulting mixture. Composition B (infra) can be prepared in a similar manner.

Compo sition B Mg / capsule Active ingredient 250 (b) Lactose B.P. 143 (c) Sodium starch glycolate (d) Magnesium stearate 420 Composition C Mg / capsule (a) Active ingredient 250 (b) Macrogol 4000 BP 350 600 The capsules can be prepared by melting the Macrogol 400 BP, by dispersing the active ingredient in the melt and filling the hard gelatin capsules in two parts with it.

Composition D Mg / capsule Active ingredient 250 Lecithin 100 Ace i te arachi s 100 450 Capsules can be prepared by dispersing the active ingredient in lecithin and arachis oil and gently filling the elastic gelatin capsules with the dispersion.

Composition (controlled release capsule) Mg / capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 Lactose BP 125 (d) Ethyl cellulose 13 513 The composition of the controlled release capsule can be prepared by extruding the mixed ingredients (a) to (c) by using an extruder, then spheronizing and extruding. The dried pellets are covered with a membrane that controls the release (d) and the hard gelatin capsule is filled in two parts.

Composition F (Enteric capsule) Mg / capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose BP 125 (d) Phthalate acetate cellulose 50 (e) Diethyl phthalate 555 The composition of the enteric capsule can be prepared by extruding the mixed ingredients (a) to (c) by using an extruder, then spheronizing and drying the extruded product. The dried pellets are covered with an enteric membrane (d) containing a plasticizer (e) and The hard gelatin capsule is filled in two parts Capsule Composition of controlled enteric coated release). The enteric capsules of composition E can be prepared by coating the controlled release pellets with 50 mg / capsule of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and Methacrylic acid methyl ester (Eudragite L). Except for Eudragite L, these polymers may also include 10% (by weight of the amount of polymer used) of a plasticizer to prevent the membrane from breaking during application or during storage. The most suitable types include diethyl phthalate, tributyl citrate, and triacetin.

Composition of intravenous injection Active ingredient 0.200 g Steryl, pyrogen-free phosphate buffer (pH 9.0) at 10 ml The active ingredient is dissolved in the phosphate buffer at 35-40 ° C, then it is completed to volume and filtered through a sterile micropore filter in sterile 10 ml glass bottles (Type 1) which are sealed with closures and seals. Composition of the intramuscular injection Active ingredient 0.20 g Benzyl alcohol 0.10 g Glycol urol 75 1.45 g Water by injection q.s. to 3.00 ml The active ingredient is dissolved in glycofurol. The benzyl alcohol is added and dissolved and water is added to 3 ml. The mixture is then filtered through a sterile micropore filter and poured into sealed sterile 3 ml glass vials (Type 1).

Syrup composition Active ingredient 0.25 g Sorbitol solution 1.50 g Glycerol 1.00 g Sodium benzoate 0.005 g Flavor 0.0125 ml Purified water q.s. to 5.0 ml The sodium benzoate is dissolved in a portion of purified water and a solution of sorbitol is added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and then completed to the required volume with purified water. Composition of the suppository Mg / sups i tor i o Active ingredient 250 Fat hard BP (Witepsol 1770 H15-Dynamite NoBel) 2020 One fifth of the Witepsol H15 is melted in a jacketed boiler, with steam at 45 ° C as maximum. The active ingredient is sieved through a 2001 m sieve and added to the molten base with mixing, when using a Silverson sieve with a cutting head, until a fine dispersion is achieved. By keeping the mixture at 45 ° C, Witepsol H15 is added to the suspension which is stirred to ensure homogeneous mixing. The total suspension is passed through a 250im stainless steel grate and with continuous agitation. Allow to cool to 40 ° C. At a temperature of 38-40 ° C, aliquots of 2.02 g of a mixture are filled with the appropriate plastic molds and the suppositories are allowed to cool to room temperature.

Composition of the pessary Mg / weighing io Active ingredient 250 (631m) Dextrose anhydrous 380 Potato starch 363 Magnesium stearate 7 1000 The above ingredients are directly mixed and pessary preparer by compressing the resulting mixture.

Transdermal composition Active ingredient 200 mg Alcohol USP 0.1 ml Hydroxyethyl cellulose The active ingredient and USP alcohol are set with hydroxyethyl cellulose and packaged in a transdermal device with a surface area of 10 cm2.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content in the following is claimed as property:

Claims (18)

1. CLAIMS 1.
2. A compound of Formula (I) or a derivative of the i < 5 m r. < OR characterized in that: P. is a phenyl-naphthyl-1-iridyl-thiazolyl-phenoxymethyl- or 1-irimidyl radical, optionally substituted by one or more selected substitutents of the prijnn or consisting of halosene, hydroxy, -alkoxy C'-Cr C-nitro cyano, -hydroxymethyl, -trifluoromethyl, -NR'JR ° and -NHS02R, wherein each P. "is independent of hydrogen or Ci-C4 alauyl, R 'is hydrogen , or C? _Cr alkyl, X is oxygen, sulfur, -WH, or -JM C? -C4 alkyl, R. 'is cyano tetrazol-5-yl or -CO ~ F. wherein P. is hydrogen or C-Cr alkyl, R 'v R - * "- c i nripn -. pririi pnt -pnipnt -p hi ri -r? ~ rjpnn ' s 1 m ..ji lo -C02H, -C02 C-C 'alkyl, -cyano, -tetrazol-5-yl, halogen, trifluoromethyl, or Ci-Cβ alkoxy. or adjacent carbon - P. v p. ~ ru - -unto with the carbon atoms to which are a foil ring of 5 to 6 members fused oocionalmte cxu contain no or two atoms of sulfur, oxygen or nitrogen, and Y is N o 2.
3. A compound in accordance with the rei indication 1, characterized norsue R ± is phenoxymethyl or phenyl optionally substituted t ~ > or r u, two, or three substituents selected from halogen, hydroxy, -alkoxy C: -c, aleuyl Ci_r, nitro, cyano, hydroxymethyl, and trifluoromethyl. 3 - A compound in accordance with the rei ^ edication "1 - rarari i nn n n r GT u? > R x e- =: ff-.pnv-i m < - ti 1 fpni 1 nn r i nri 31 TTi nl-? h? t i fn i d? DO fluorine, bro, ethyl, or trifluoroethyl.
4. A compound according to any one of the rei indications 1-3, characterized oorsue R 'is hydrogen or methyl
5. 5. A compound according to any one of the rei indications 1-4, characterized in that R 'is hydrogen.
6. 6. A compound according to any of the rei indications 1-5, characterized in that X is NH. .
7. A compound according to any of the rei indications 1-6, characterized in that R ~ is C02H.
8. 8. A compound according to any one of the rei indications 1-7, characterized in that at least one of R4 and RX are both hydrogen.
9. 9. A compound according to any one of the rei indications is 1-8, characterized in that at least one of R4 and R "are both hydrogen.
10. 10. A compound according to any one of the rei indications 1-9, characterized in that Y is CH.
11. 11. A compound according to claim 1, characterized in that R "is phenoxymethyl or phenyl substituted by a chloro, fluoro, bromo, methyl, or trifluoromethyl; R is hydrogen or methyl; X is NH, or NCH3; RX 'is C02H and Y it's CH
12. 12. A compound selected from the group consisting of: (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1, 1 '-biphenyl] -3-carboxylic; dimethyl ester of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] to inol ethyl] amino] - [1,1'-biphenyl] -2,4-dicarboxylic acid; ? c + - o and mpf í 1 í 'n HoT ápi rlp / En -. ^' -,. ? -. . ? -! ^ -chlorophenyl) -2-hydroxyethyl] to ino] ethyl] amino] - [1,1'-bifeyl] -2-methyl-5-carboxylic acid; Figure imgf000014_0001 (R) - ^ '-. r? -..? - /' - cyclophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1, 1 ' -biphenyl] -3, -dicarboxylic; ω-methyl-methyl aridi P- ^ '- <? - • <? - i "-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [ 1,1 '-bife il] -3-chloro-4-carboxylic acid; (R) -3 '- [[2- [[2- (3,5-Dichloropheyl) -2-hydroxyethyl] -α-ene] ethyl] amino] - [1,1' -biphenyl] -3 methyl ester -carboxylic; (R) -3 '- [[2 - [[2- (3,5-dichlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid; (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1, 1-biphenyl] -3-carboxylic acid; 2-methyl ester of (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] ao] - [1,1' -bifenill-2, 4] -dicarboxilic; a r- i H (D _ '_ [r9-p9-C-rl nr? pheni l-2-hydroxyethyl] amino] ethyl] amino] - [1,1' -biphenyl] -2, -dicarboxylic acid; RI - R '- R - R - N - N - N -Forii-N-hydroxyethyl] amino] ethyl] amino] - [1,1' -biphenyl] -2-methyl-5-carboxylic acid; (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-chloro-4-carboxylic acid; (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] ami or] ethyl] amino] - [1,1' -biphenyl] -3,4-dicarboxylic acid; (R) -3 '- [[2 - [(2-hydroxy-3'-phenoxypropyl) amino] and yl] amino] - [1,1'-biphenyl] -3-carboxylic acid (R) -3' - [2 - [[2- (3-chloropheyl) -2-hydroxyethyl] amino] ethoxy] - [1,1'-biphenyl] -3-carboxylic acid; 3 '- [[2R - [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] - [1,1'-biphenyl] -4-carboxylic acid; ar-i Hn ^ '. [T91.- r Í9- í l? I-? F »n? 1 > - '' R-hydroxyethyl] amino] propyl] amino] - [1,1'-biphenyl] -2-carboxylic; 3 '- [[2R- [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] - [1,1'-biphenyl] -2,4-dicarboxylic acid; 5- [3- [[2R- [[2- (3-chlorofenyl) -2R-hydroxyethyl] amino] propyl] amino] phenyl] -3-pyridylcarboxylic acid; 2- [3 - [[2R - [[2- (3-chlorophenyl) -2R-hydroxyethyl] aminolpropyl] amino] phenyl] -3-pyridinecarboxylic acid; (R) -5- [3 - [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -2,3-dihydro-7-benzofurancarboxylic acid; (R) -5- [3 - [[2 - [[2- (3-Chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -3-pyridinecarboxylic acid; . aci or (R) -2- r ^ r r? -r r? - c.-rl-nfoni 1) -9-hydroxyethyl] amino] ethyl] amino] phenyl] -4-pyridinecarboxylic acid; hydroxyethyl] mino] ethyl] a ino] - [1,1'-phenyl] -3- (5-tetrazolo); (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carbo ityl; (R) -2- [3- [[2- [[2- (3-chloropheni-1) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -2-pyridinecarboxylic acid; or pharmaceutically acceptable derivatives
13. 13. A compound selected from the group consisting of: (R) -5- [3 - [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -3-pyridinecarboxylic acid; 3 '- [[2R - [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino]] - [1,1'-biphenyl] -2,4-dichloroboxylic acid; acid (R ^ -3 '- [[2R - [[(2-ddrox? -3-phenoxypropyl) amino] propyl] amino]] - [1, 1'-biphenyl] -3-carboxylic acid; a < id ^ R1-R1-R1-R1-RN-RNPP1-2-hydroxyethyl] amino] ethyl] amino]] - [1,1'-biphenyl] -2-methyl-5-carboxylic acid; (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino]] - [1,1'-biphenyl] -3-carboxylic acid or a derivative pharmaceutically acceptable
14. 14. A compound according to any one of claims 1 to 13 characterized by its use in therapy.
15. 15. The use according to any one of claims 1-13 in the manufacture of a medicament for the treatment of a mammal, including man, of the conditions susceptible to amelioration by an atypical beta adrenoceptor agonist.
16. 16. A method for the treatment of a mammal, including man, of the conditions susceptible to the amelioration by an atypical beta adrenoceptor agonist characterized in that it comprises the administration of an effective amount of a compound according to any one of the rei indications. 1 to 13 or a pharmaceutically acceptable salt thereof.
17. 17. A pharmaceutical composition characterized in that it comprises a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers.
18. 18. A process for the preparation of the compound of Formula (I) characterized in that it comprises: (A) the deprotection of a compound of Formula (II), (ll) or; (B) the interconversion of an additional compound of Formula (I) or; (C) the reaction of the Formula compound (III) with a compound of Formula (IV), followed by Step (A) without the purification of intermediates; R (II!) (IV) (D) the reaction of the compound of Formula lil) with a compound of Formuia (IX) (VIII) (IX) SUMMARY OF THE INVENTION The present invention provides therapeutic biaryl derivatives of the formula (I) and pharmaceutically salts thereof: wherein R "1- is a phenyl, naphthyl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C: -Ce alkoxy, C: -C. nitrocyano, hydroxymethyl, trifluoromethyl, -NR ', R6 and -NHS02Rβ, wherein each R ° is independently hydrogen or Ci-C ^ alkyl; R 'is hydrogen, or Ci-Cs alkyl, X is oxygen, sulfur, -NH, or -N C1-C4 alkyl, R "is cyano, tetrazol-5-yl, or -COcR' wherein R 'is hydrogen or C -C alkyl, R "and R" are independently hydrogen, C? -Cc alkyl, -C02H, -C02 C? -Calkyl, cyano, tetrazole-5i, halogen, trifluoromethyl, or C-alkoxy; CG, or when R '1 and Rb are attached to the adjacent carbon atoms, R * and RD can, together with the carbon atoms to which they are attached, form a ring provided with 5 to 6 optionally fused members containing one or two atoms of sulfur, oxygen or . nitroge or, and Y is N or CH, to the processes for its preparation and its use in the treatment of diseases-susceptible to the amelioration by the treatment with beta-3 adrenoceptor agonists