WO1997046553A1 - Thrombin inhibitors - Google Patents

Abstract

The present invention provides a compound of general formula (I) in which Y is a primary or secondary amino group; R2 is the residue of a natural or synthetic amino acid; R3 is hydrogen or a C1-C8 alkyl chain which may be substituted by hydroxy or halogen; and X is (CH2)n where n is 1, 2, or 3, or is CH2N or represents a fused phenyl ring which is optionally substituted by one or two methoxy groups or a salt thereof.

Description

Thrombin Inhibitors

The present invention relates to new compounds which have activity as inhibitors of thrombin.

Accordingly the present invention provides a compound of the general formula I

in which Y is a primary or secondary amino group; R₂ is the residue of a natural or synthetic amino acid; R₃ is hydrogen or a Cι-C₈ alkyl chain which may be substituted by hydroxy or halogen; and X is (CH₂)n where n is 1, 2, or 3, or is CH₂N or represents a fused phenyl ring which is optionally substituted by one or two methoxy groups or a salt thereof.

As a primary or secondary amino group, Y may have the formula

R

A^{X N}

I H

R in which A and R are absent or A is a methylene or ethylene group, and R is hydrogen, halogen, azido, COOR₈ where Rβ is H or alkyl, OR₉ where R₉ is H, 2 alkyl, optionally substituted hydroxyalkyl, optionally substituted carboxyaikyi, optionally substituted amidoalkyl, SO∑ alkyl, SO₂ aryl, or NR10R11 where R10 and R n are independently H, alkyl which is optionally substituted and/or optionally interrupted by O or is CH3SO2, or together with the nitrogen atom form an optionally substituted ring which may contain another hetero atom or R is SR₁₂ where R1₂ is hydrogen or hydroxyalkyl; B is CH or is absent provided that when B is absent, A and R are also absent; Ri is hydrogen, alkyl, alkyl optionally substituted and/or optionally interrupted by O, S, carboxyl aminocarbonyl, or carbonylamino or is an optionally substituted phenyl ring or a phenyl ring containing one or more heteroatoms or a cyclohexane or bicyclic ring containing one or more hetero atoms; m is 0, 1 or 2 and when m is 1 and R is H, A may form a cyclopropane ring with the C atom to which R^ is attached.

When R₁0 and Rn represent alkyl, the alkyl may be substituted by OH, COORβ where R_β is H or alkyl, carbonyl or amide groups or by a heterocyclic ring.

When Ri is a substituted alkyl group it may be substituted by OH, substituted hydroxyl, carboxyl, carboxyaikyi, phenyl or substituted amino. Preferably the substituent is in a terminal position.

When Ri is a substituted phenyl ring it may be substituted by one or more halogen or alkyl groups or one or more groups OR₄, SR₅, NR₆R7 or COORβ where each of R₄ to R_β is H or alkyl or NR₆R7 is NO₂.

Halogen atoms in R and/or R₃ may be fluorine, chlorine, bromine or iodine, but preferably fluorine or chlorine. Examples of the groups R include H, F, CI, N₃, OH, OCH₃. OSO2CH3, OSO₂ benzyl,

OCH₂CH₂OH and its 2-pyranyl ether, OCH_∑COOH and its tert.-butyl ester, OCH2CON(CH₃)₂, OCH₂CONH(CH₂)2OH, the corresponding morpholide OCH₂COMθ h, COOH and its methyl and tert.-butyl esters, SH, S(CH₂)₂ OH, S(CH₂)₃ OH, NH₂, NHCH_3l NHC2H5, N(CH₃)C₂Hs. NHC₃H₇(n), NHC₄H₉, NHCH2CH2OH, NHCONH2, NHCONHC₂H₅, NHCH₂CH₂OCH₃, N(CH₂CH₂OCH₃)₂, NHCOCH₃, N(CH₃)CH₂COOH, NHCH₂COOH and its tert.¬ butyl ester, NHCH₂ pyridyl, N(CH₃)₂, N(C₂H₅)₂, pyrrolidinyl, piperidinyl, 4- hydroxypiperidinyl, moφholinyl, thiomoφhplinyi.

When R10 and Rn form a ring together with the nitrogen atom to which they are attached, the ring may be, for example, a piperidine, py olidine, moφholine, thio oφholine or piperazine ring, which may be optionally substituted.

When Ri is or contains a ring system, the ring may be, for example, a phenyl, cyclohexane, benzothiazole, indole, indane, naphthalene, thiophene or thiazole ring.

In many cases Ri is derived from an amino alcohol, for instance, those obtained from optionally ring-substituted phenylalanines, tryptophans and pyridylalanines.

Examples of the group Ri include phenyl, cyclohexyl, 4-methoxyphenyl, 4- ethoxyphenyl, 3-4-di-methoxyphenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 4- hydroxyphenyl, 4-nitrophenyl, 4-aminophenyl, 4-methylphenyl, 2-pyridyl, thiazolyl, indolyl, methylthiomethyl, n-butyl.

Examples of the group Rι-(CH₂)_m include n-propyl, n-butyl, n-pentyl, iso- butyl, iso-pentyl, 5-hydroxy-pentyl, caΦoxylethyl, 4-phenylbutyl, n- butylcarbamoylethyl, 2-indanyl, 4-methylbenzyl, 2-aminobenzyl, 4- carboxybenzyl and its methyl ester, 2-pyridylmethyl, phenylethyl, 4- hydroxyphenylethyl and its methyl ether, 2-aminophenylethyl, carboxyundecyl, hydroxyethyloxyethyl.

As an amino acid residue, R2 may be derived from the amino acids phenylalanine, tyrosine, dopa and its ethers such as the methylenedioxy ether, p-aminophenylalanine, p-nitrophenylalanine, naphthylalanine, benzothiazolylalanine, thiazolylalanine, cyclohexylalanine, the pyridylalanines, tryptophan, and fused 6/5 membered ring systems linked through the 6-membered ring and where the 5-membered ring contains one or more hetero atoms.

Examples of the groups R₂-CH₂- include 2-benzthiazolylmethyl, 2- benzoxazolylmethyl, 2-benzimidazolylmethyl, 2-naphthylmethyl, 2-(3- and 4-)pyridylmethyl, benzyl, 4-hydroxy benzyl, 4-methoxy benzyl, 4- ethoxybenzyl, cyclohexylmethyl, 4-nitrobenzyl, 4-aminobenzyl, 4- methylaminobenzyl, 4-dimethylaminobenzyl, 4-ethylaminobenzyl, 4- fluorobenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, 3,4- methylenedioxybenzyl, 4-acetylaminobenzyl, 4-formylaminobenzyl, 4- hydroxyaminobenzyl, 3-hydroxy-4-methoxybenzyl, 3-amino-4-hydroxybenzyl, 3-amino-4-methoxybenzyl, 4-thiazolylmethyl

The group R₃ preferably has 2 or 3 carbon atoms and may be terminally substituted by hydroxy, fluorine or chlorine.

X is preferably CH₂N or (CH₂)₂. When X is CH N the two N atoms in the ring are preferably in the para positions and R₃ is then preferably attached to the N atom in X. Preferably A-R is present, m is 1, A is -CHr and X is (CH₂)₂.

There are two chiral centres in the compounds of the invention. It is preferred that the compounds have the (S) configuration at each of the chiral centres. Compounds having the (R) configuration are also included within the scope of the invention especially when it is bome in mind that the priority rules for naming compounds result in an (R) configuration in some cases e.g. where Ri is a methylthiomethyl group.

The compounds of the invention can be considered as being in four parts, A, an amine moiety which is

( I I I

B, a pyridine moiety which is

C, an aminoacid moiety Aa which is

CH

and D, a base which is

The compounds of the invention may be made by various processes as outlined in Methods 1 to 3 below

Synthetic Schemes

Method 1 : (D→ C-D→ B-C-D→ A-B-C-D)

Base + N-protected aminoacid i coupling

N-protected aminoacyl base i deprotection

aminoacyl base

1 chloropyridine sulfonyl chloride

chloropyridinesulfonyl-aminoacyl-base 1 amine

aminopyridinesulfonyl-aminoacyl-base

Method 2: (B → B-C → B-C-D → A-B-C-D)

chloropyridine sulfonylchloride + aminoacid (derivative) i coupling

chloropyridine sulfonyl-aminoacid (derivative) 1 deprotection (if needed) chloropyridine sulfonyl-amino acid i couple with base

chloropyridine sulfonyl-aminoacyl-base i amine

aminopyridine sulfonyl-aminoacyl-base

Method 3: (B→ B-C→ A-B-C→ A-B-C-D)

This is similar to Method 2 except that the last two stages are interchanged.

In all cases it is then possible to convert one amino moiety into a different amino moiety.

In the above Methods 1 , 2 and 3, the C-D coupling reaction may be carried out by reaction of the amino acid with the base and where the amino acid and the base are optionally protected. The reaction of the amino acid with the base is carried out for instance as are coupling reactions of amino acids in the preparation of peptides and according to methods of protection, activation, coupling and deprotection or partial deprotection described in the literature (Houben Weyl, Methoden Der Organichen Chemie Vol. 15 Parts 1 & 2).

For instance the aminoacyl base compounds can be prepared by protecting the α-amino group of the amino acid via acetylation, formylation, phthaloylation, trifluroacetylation, p-methoxybenzyloxycaΦonylation, benzoylation, benzyloxycaΦonylation, t-butyoxycarbonylation, arylsulfonylation, or tritylation and then condensing the formed N^β- substituted amino acid with the base to give a protected form of the aminoacyl base by a conventional process such as the acid chloride method, azide method, mixed anhydride method, activated ester method, or carbodiimide method, with or without additives such as hydroxysuccinimide, hydroxybenztπazole, diethyl phosphite or the like, and thereafter selectively removing the protective groups to give the desired compound

Altematively the reaction may be earned out by the condensation of an N^β- arylsulfonyl aminoacyl halide, preferably a chloπde, a mixed anhydπde, or a similar activated species deπved in situ from the ammo acid with at least an equimolar amount of the base The condensation reaction can be earned out with or without an added solvent in the presence of a base Solvents such as dimethylformamide (DMF) or dimethylacetamide (DMF) or halogenated solvents such as chloroform or dichloromethane may be used The amount of the solvent to be used is not cπtical and may vary from about 5 to 100 times the weight of the N°-arylsulfonyl ammo acid (VI) In the other cases the activating principle such as diethyl phosphite may be the solvent

When the activated species is a pyπdyl-sulfonyl aminoacyl halide it may be prepared by reacting a pyπdyl-sulfonyl am o acid VII with at least an equimolar amount of a halogenating agent such as thionyl chloπde, phosphorus oxychloπde, phosphorus tπchloπde, phosphorus pentachloπde or phosphorus tπbromide. The halogenation may be earned out with or without an added solvent The preferred solvents are chloπnated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxan Preferred reaction temperatures are in the range of -10°C to room temperature The reaction time is not cπtical, but vanes with the halogenating agent and reaction temperature In general, a peπod of 15 minutes to 5 hours is operable

Altematively the reaction may include reaction of the ammo acid with the base in the presence of condensing agent such as a carbodiimide, for instance dicyclohexyl-caΦodumide in the presence or absence of an activating species such as hydroxybenzotπazole or diethyl phosphite and in the presence of a base The base used in the above reactions may be either an organic base such as Huenig Base, tnethylamine, N- methylmoφholine, or pyndine or an inorganic base such as sodium hydroxide or potassium carbonate. The condensation reaction may be carried out at a temperature between -10° C and the boiling point of the solvent. Preferred condensation reaction temperatures are in the range from -10° C to room temperature. The reaction time is not critical. In general, a period of from 5 minutes to 10 hours is operable.

The B-C reaction may be carried out for instance under conditions known for introducing arylsulfonyl groups onto amino substituted compounds.

For instance the reaction may be carried out by the condensation of an aminoacid or aminoacyl amide with a substantially equimolar amount of 4- chloropyridine-3-sulfonyl chloride. The condensation reaction is generally effected in a suitable inert solvent in the presence of an excess of a base, such as an organic base e.g. triethylamine, di-isopropylethylamine, pyridine, N-methyl or N-ethyl moφholine or a solution of an inorganic base e.g. sodium hydroxide or potassium carbonate, at a temperature of 0°C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours. The preferred solvents for the condensation include dichloromethane or other chlorinated hydrocaΦons, DMF, benzene-diethyl ether, diethyl ether- water and dioxan-water.

The A-B reaction may be carried out by the condensation of the amine with a chloropyridine sulfonyl compound which already carries the aminoacid moiety and optionally the base as well.

In some cases the amine moiety A may be complex and be derived from 2 or 3 components such as a-b-c or b-c. In these cases the amine can be pre¬ formed and reacted with the chloropyridine compound B-C-D to form A-B-C- D. Altematively the amine may be reacted with B-C-D as b-c followed by adding a or it may be reacted as c, then a-b or as c then b then a. In all cases, dependent on the actual structures, it is possible to have protection, or proceed without it. Thus the compounds of the invention may be formed:- (i) a-b-c + B-C-D → a-b-c-B-C-D

(ii) b-c+B-C-D → b-c-B-C-D, then couple with a → a-b-c-B-C-D

(iii) c+B-C-D → c-B-C-D, then activate as mesylate and displace with a-b → a-b-c-B-C-D

(iv) c+B-C-D → c-B-C-D, then activate as mesylate and displace with b (or a derivative which is then deprotected) → b-c-B-C-D and then couple with a → a-b-c-B-C-D

When the product of formula I is obtained from the condensation reaction in protected form, it may be purified by extraction and the solvent removed by such standard means as evaporation under reduced pressure and then converted to the compound of formula I by removing the protecting group by means of acidolysis or hydrogenolysis. The acidolysis is generally effected by contacting the protected form of I and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether e.g. tetrhydrofuran or dioxan, an alcohol e.g. methanol or ethanol or acetic acid at a temperature of -10°C to 100°C, and preferably at room temperature for a period of 30 minutes to 24 hours. The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying.

Because of the use of excess acid, the products are in certain cases the acid addition salts of the compounds of formula I, which can easily be converted to a free amide by neutralisation. When the protected compound of formula I contains the benzoxycaΦonyl protection group the removal is readily accomplished by hydrogenolysis. At the same time any benzyl ester moiety is converted to the caΦoxyl group by the hydrogenolysis. The hydrogenolysis is effected in an inert reaction solvent, e.g. methanol, ethanol, tetrahydrofuran or dioxan optionally in the presence of an acid such as acetic acid and in the presence of a hydrogen-activating catalyst e.g. Raney nickel, palladium or platinum, in a hydrogen atmosphere at a temperature of 0°C to the boiling temperature of the solvent for a period of 2 hours to 120 hours. The hydrogen pressure is not critical, and atmospheric pressure is sufficient. The products of formula I are isolated by filtration of the catalyst followed by evaporation of the solvent. They may be purified by trituration or recrystallisation from a suitable solvent, such as ethyl acetate, diethyl ether-tetrahydrofuran, diethyl ether-methanol and water-methanol, or may be chromatographed on silica gel, ion-exclusion gels or reverse-phase liquid chromatography supports.

In those cases where the initial product of formula I contains a protected caΦoxylic acid or alcohol, it is well recognised in the art that the caΦoxylic acid or alcohol can be prepared from the ester derivative by conventional hydrolysis or acidolysis methods. The conditions under which esterification, hydrolysis or acidolysis can be carried out will be apparent to those skilled in the art.

The compounds (I) of this invention in certain cases form acid addition salts with any of a variety of inorganic and organic acids. Some of the compounds containing a free caΦoxyl group form salts with any of a variety of inorganic and organic bases.

The product of the reactions described above can be isolated in the free form or in the form of salts. In addition, the product can be obtained as acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like. In a similar manner, the product can be obtained as salts by reacting the free carboxyiic acid with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.

Likewise, treatment of the salts with a base or acid results in a regeneration of the free amide.

The chloropyridine sulfonyl chloride may be prepared from the corresponding hydroxypyridine sulfonic acid by chlorination.

Examples of suitable chlorinating agents include phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosgene, benzotrichloride, thionyl chloride, chlorosulfonic acid, sulfur dichloride, sulfur and chlorine and chlorine.

Suitable solvents for the reaction include trifluoroacetic acid, dimethylformamide (DMF), dimethylacetamide (DMA), 1 ,3-dimethyl-2- imidazolidinone (DMID), and pyridine.

The reaction is conveniently carried out between -10°C and the boiling point of the solvent. It is advantageous to disperse or dissolve the sulfonic acid or its salt in the solvent whilst applying ultrasound.

After the reaction is complete, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.

The compounds of the formula I provide interesting compounds which contain potent and orally bioavailable inhibitors of serine proteases, especially thrombin. The compounds of the present invention are useful in compositions, combinations and methods for the treatment and prophylaxis of various diseases attributed to thrombin-mediated and thrombin-associated functions and processes. These include myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, peripheral arterial occlusion, restenosis following arterial injury or invasive cardiotogical procedures including percutaneous transluminal coronary angioplasty, atrial fibrillation, acute or chronic atherosclerosis, edema and inflammation, various cell regulatory processes (e.g. secretion, shape changes, proliferation), cancer and metastasis, and neurodegenerative diseases.

The thrombin inhibitors of the present invention may be formulated into pharmaceutically useful compositions, such as by mixing with a pharmaceutically acceptable carrier or diluent. These compositions may be used for treating or preventing thrombotic diseases in a patient.

According to an alternate embodiment of the present invention, the thrombin inhibitors may be employed in compositions for preventing and/or treating thrombotic disease, and for decreasing the dosage of a thrombolytic agent required to establish reperfusion or prevent reocclusion in a patient. Additionally, the thrombin inhibitors of this invention may be used in compositions for decreasing reperfusion time or the incidence of acute reocclusion in a patient treated with a thrombolytic agent. These compositions may comprise a pharmaceutically effective amount of a thrombin inhibitor of the present invention and a pharmaceutically effective amount of a thrombolytic agent.

In these compositions, the thrombin inhibitor and the thrombolytic agent work in a complementary fashion to dissolve blood clots, resulting in decreased reperfusion times and incidence of acute reocclusion in patients treated with them. The thrombolytic agent dissolves the clot, while the thrombin inhibitor prevents newly exposed, clot-entrapped or clot-bound thrombin from regenerating the clot. The use of the thrombin inhibitor in the compositions of this invention advantageously allows the administration of a thrombolytic reagent in dosages previously considered too low to result in thrombolytic effects if given alone. This avoids some of the undesirable side effects associated with the use of thrombolytic agents, such as bleeding complications.

Thrombolytic agents which may be employed in the combinations and compositions of the present invention are those known in the art. Such agents include tissue plasminogen activator purified from natural sources, recombinant tissue plasminogen activator, streptokinase, urokinase, prourokinase, anisoiated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, hybrids of the above and known, biologically active derivatives. The thrombin inhibitor and the thrombolytic agent may be in the same or in separate dosage forms which are administered separately, but concurrently or sequentially. In sequential administration, the thrombin inhibitor may be given to the patient at a time from 5 hours before to 5 hours after administration of the thrombolytic agent. Preferably, the thrombin inhibitor is administered to the patient at a time from 2 hours before to 2 hours after administratiorrof the thrombolytic agent.

The compounds of the invention may also be used in combinations and compositions with other antithrombotic drugs such as aspirin, fibrinogen receptor blockers, platelet glycoprotein llb/llla antagonists, platelet aggregation inhibitors and the like.

The compositions of the invention may be administered to a patient in various ways e.g. enterally such as orally or rectally, parenterally or topically. The compositions will be formulated using adjuvants and diluents suitable for the desired method of administration. Thus the compositions may be administered intravenously or intra-arterially as bolus or by continued infusion, intramuscularly - including paravertebrally and periarticulaiiy - subcutaneously, intracutaneously, intra-articularly, intrasynoviaily, intrathecally, intra-lesionally, periostally or by oral, nasal or topical routes. In addition they may be given by either passive or active methods, including by iontophoresis.

Parenteral compositions are preferably administered intravenously either in a bolus form or as an infusion. For parenteral administration, the thrombin inhibitor may be either suspended or dissolved in a sterile vial or ampoule and sealing. Preferably, adjuvants such as a local anesthetic, preservatives, stabilizers, solution promoters and/or buffers may also be dissolved in the vehicle. The composition may then be frozen and lyophilized to enhance stability. In the case of suspensions, a surfactant or wetting agent and/or other adjuvant as mentioned above may be included in the composition to facilitate uniform distribution of its components.

Tablets and capsules e.g. gelatin capsules for oral administration may comprise the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, soΦitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salts and/or polyethylene glycol; for tablets also c) binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellolose and/or polyvinylpyrrolidone; if desired, d) disintegrants, e.g. starches, starch derivatives such as sodium starch glycolate, croscaπmellose, agar, algiπic acid or its sodium salt, or effervescent mixtures; e) wetting agents such as sodium lauryl sulphate; and/or f) absorbents, colourants, flavours and sweeteners. Suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents.

Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstruction with water or another suitable vehicle before use. Such liquid preparations may contain conventional additives. These include suspending agents; such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylceilulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, polyethylene glycols, or acacia; non-aqueous vehicles, such as almond oil, fractionated coconut oil, and oily esters; and preservatives, such as methyl or propyl p-hydroxybenzoate or sorbic acid.

Compositions formulated for topical administration may, for example, be in aqueous jelly, oily suspension or emulsified ointment form.

Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.

Transdermal systems may be made by applying an adhesive layer to a base layer, e.g. a peel-off protective layer, applying a reservoir to the base layer, the reservoir containg the active ingredient and optionally a polymeric material for forming a porous or permeable membrane and/or a penetration enhancer, and then applying an impermeable outer layer on top.

The dosage of active compound administered is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, and on the form of administration.

A preferred pharmaceutically effective dose of the thrombin inhibitor of this invention is from 0.01 mg/kg body weight of the patient to be treated to 50 mg/kg body weight, preferably from 0.1 to 1.0 mg/kg.

The amount used depends on the method of administration. Normally lower amounts are needed for parental administration than for enteral administration. The dose for infusions however may be higher than the range given, preferably from 0.01 to 1.0 mg/kg/hr. When a thrombolytic agent is also used a pharmaceutically effective dose of the thrombolytic agent may be between 10% and 80% of the conventional dosage range, i.e. the dosage used when that agent is employed in a monotherapy.

The compounds of the invention may also be used in the form of conjugates with materials such as polyethylene glycol. This would modify the pharmacokinetic properties of the compounds and result in lower doses being needed, or less frequent doses.

The thrombin inhibitors of the invention may also be used in compositions and methods for coating the surfaces of invasive or extra-coφoreal devices, resulting in a lower risk of clot formation or platelet activation in patients receiving or using such devices. Surfaces that may be coated with the compositions of this invention include, for example, prostheses, artificial valves, vascular grafts, stent tubing, membranes and catheters. Methods for coating these devices are known to those of skill in the art. These include chemical cross-linking or physical adsoφtion of the thrombin inhibitor-containing compositions on to the surfaces of the devices.

Compositions containing the thrombin inhibitors of this invention may also be used in the treatment of tumor metastases, as indicated by the inhibition of metastatic growth. Examples of metastatic tumors which may be treated by the thrombin inhibitors of this invention include carcinoma of the brain, carcinoma of the liver, carcinoma of the lung, osteocarcinoma and neoplastic plasma cell carcinoma.

Compositions containing the thrombin inhibitors of the invention may also be used to inhibit thrombin-induced endoethelial cell activation, including the repression of synthesis of mediators, including platelet-activating factor (PAF), eicosanoids, endothelial-derived relaxing factor (EDRF) and endothelin, by endothelial cells. The compositions have important applications in the treatment of diseases characterised by thrombin-induced inflammation and edema, which is thought to be mediated by PAF. Such diseases include adult respiratory distress syndrome, septic shock, septicemia, reperfusion damage, and for treating or preventing septicemia and other diseases.

The thrombin inhibitors of the invention or compositions comprising them, may also be used as anticoagulants for extracoφoreal blood, for instance in such processes as dialysis procedures, blood filtration, or blood bypass during surgery at doses from 0.01 to 1.0mg/kg as well as in blood products which are stored extracoφoreaily for eventual administration to a patient and blood collected from a patient to be used for various assays. Such products include whole blood, plasma, or any blood fraction in which inhibition of coagulation is desired.

The amount or concentration of thrombin inhibitor in these types of compositions is based on the volume of blood to be treated or, more preferably, its thrombin content, and may be from 0.01mg/60ml of extracoφoreal blood to 5mg/60ml of extracoφoreal blood.

The thrombin inhibitors of this invention may also be used to inhibit clot- bound thrombin, which is believed to contribute to thrombus growth and clot accretion, and to prevent thrombus extension. This is particularly important because commonly used anti-thrombin agents, such as heparin and low molecular weight heparin, are ineffective against clot-bound thrombin.

Finally, the inhibitors of this invention may be used for treating neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, inflammatory diseases and cerebral ischaemia.

The invention is illustrated by the following Examples, in which the abbreviations used have the following meanings. ABBREVIATIONS

DAST Diethylamino sulfur trifluoride

DME Ethylene glycol dimethyl ether

DMF N,N-Dimethylformamide

DMSO Dimethyl sulfoxide

Huenig Base Ethyldiisopropylamine

Ishikawa reagent Diethyl-(1 , 1 ,2,3,3,3-hexafluoro-propyl)-amine

NMM N-Methyl moφholine

PyBOP Benzotri azol- 1 -y l-oxy-tri s- pyrrolidinophosphonium hexafluorophosphate

TBAF Tetrabutylammonium fluoride

THF Tetrahydrofuran

Intermediate 1 - 2(S Amino-3-(4-fluoro-Dhenvπ-DroDan-1-ol

2(S)-Amino-3-(4-fluoro-phenyl)-propionic acid (504mg) is suspended with stirring in dry THF (10ml) and borane/THF complex (1M, 5.5ml) is added over a period of 5 minutes. The mixture is stirred at 20°C for 18 hours and a solution of acetic acid in methanol, (1:4, by vol., 20ml) is added. Solvents are removed by rotary evaporation to give a yellow oil which is purified by spinning band chromatography on silicagel (layer thickness 2mm) using- portions (100ml) of chloroform:ethanol (9:1 then 7:3, by vol.) as eluant to give pure 2(S)-amino-3-(4-fluoro-phenyl)-propan-1-ol as a white solid. It has a 1H NMR spectrum consistent with the claimed structure. Intermediate 2 - 2-[4-(2(S)-Amino-3-phenyl-propyl)-piperazin-1-yl}-ethanol

a) Methanesulfonic acid 2(S)-benzyloxycaΦonylamino-3-phenyl-propyl ester (1g) and 2-piperazin-1-yl-ethanol (1.78g) are dissolved in ethanol (80ml) and the solution is heated at reflux for 48 hours. The solvent is removed by rotary evaporation and the resulting oil purified by chromatography on a column of silicagel using chloroform:methanol (19:1 then 37:3, by vol.) as eluant to give 2-[4-(2(S)-benzyloxycaΦonylamino-3-phenyl-propyl)-piperazin-1-yl]-ethanol.

b) 2-[4-(2(S)-BenzyloxycaΦonylamino-3-phenyl-propyl)-piperazin-1-yl]- ethanol (3.4g) is dissolved in methanol (300ml) and hydrogenated (1 bar) in the presence of palladium on charcoal (10% w/w, 500mg) for 27 hours at 20°C. The catalyst is removed by filtration and the filtrate dried by rotary evaporation to give 2-[4-(2(S)-amino-3-phenyl-propyl)-piperazin-1-yl]-ethanol as a light yellow solid.

Intermediate 3 - 2-{2-[4-(2(S)-Amino-3-phenyl-propyl)-piperazin-1-yl]-ethoxy}- ethanol

Analogously as described for the synthesis of Intermediate 2 but using 1-(2- hydroxyethyloxy-ethyl)-piperazine in place of 2-piperazin-1-yl-ethanol is prepared the title compound as a white solid. It has a 1 H NMR spectrum consistent with the claimed structure.

Intermediate 4 - 2(S)-Amino-3-(4-ethoxy-phenyl)-propan-1-ol

2(S)-tert.-Butoxycarbonylamino-3-(4-ethoxy-phenyl)-propionic acid (4.8g) is dissolved in dry THF (25ml) and borane:THF complex (1M, 98ml) is added with stirring under an atmosphere of nitrogen at 0°C over a period of 30 minutes. The mixture is stirred at 20°C for 64 hours, aqueous acetic acid (10% by vol., 30ml) is added and solvents are removed by rotary evaporation to give a white slurry which is re-evaporated to dryness from solution in portions (x2) of ethanol (20ml) to yield a colourless syrup. This is purified by chromatography on a column of silicagel using mixtures of chloroform: methanol (from 19:1 to 10:10 in 5% increments, by vol.) to give

2(S)-amino-3-(4-ethoxy-phenyl)-propan-1-ol which contains some of the corresponding acid as impurity (confirmed by 1 H and 13C NMR spectra).

Intermediate 5 - N-(2(S)-Amino-3-phenyl-propyl)-methanesulfonamide

a) 1 (S)-Aminomethyl-2-phenyl-ethyl caΦa^'mic acid benzyl ester (4.7g) and triethylamine (5.8ml) are dissolved in dichloromethane (100ml) and placed under an atmosphere of nitrogen. The solution is cooled to 0°C and methane sulfonyl chloride (1.54ml) is added. The mixture is stirred at 0°C for 30 minutes, further portions of methane sulfonyl chloride (0.26ml) and triethylamine (1.2ml) are added and the mixture is stirred for 16 hours at 20°C. Dichloromethane (100ml) is added and the solution is washed with aqueous hydrochloric acid (200ml), brine (200ml), dried (MgSO-ι) and solvent removed by rotary evaporation to afford pure [1(S)-(methanesulfonylamino- methyl)-2-phenyl-ethyl]-caΦamic acid benzyl ester as a white solid. It has 1H and 13C NMR spectra consistent with the claimed structure.

b) [1(S)-(Methanesulfonylamino-methyl)-2-phenyl-ethyl]-caΦamic acid benzyl ester (5.6g) is dissolved in a mixture of aqueous hydrochloric acid (10ml), ethanol (300ml) and dichloromethane (2ml) and hydrogenated (1 bar) in the presence of 10% palladium on charcoal (10%w/w, 600mg) for 2 days at 20°C. Catalyst is removed by filtration and the solvents removed by rotary evaporation. The residue is partitioned between aqueous sodium hydroxide solution (1M, 200ml) and dichloromethane (200ml) and the organic phase is washed with brine (400ml), dried (MgSO ) and solvent removed by rotary evaporation to afford pure N-(2(S)-amino-3-phenyl-propyl)-methanesulfonamide as a white solid. It has 1H and 13C NMR spectra consistent with the claimed structure.

Intermediate 6 - Piperidine-4-carboxylic acid propylamide

a) Piperidine-1 ,4-dicarboxylic acid mono-tert.-butyl ester (11.04g) is dissolved in dichloromethane (200ml) and 1 ,1-carbonyl di-imidazole (17.9g) followed by propylamine (9.4ml) are added to the stirred solution under an atmosphere of nitrogen. The mixture is stirred at 20°C for 16 hours, washed with aqueous citric acid solution (3 x 200ml), saturated aqueous sodium hydrogen carbonate solution (200ml) and brine (200rhl), dried (MgSO₄) and solvent removed by rotary evaporation to afford pure 4-propylcaΦamoyl-piperidine-1- carboxylic acid tert.-butyl ester as a white solid. It has 1 H and 13C NMR spectra consistent with the claimed structure. [M+H]⁺ = 271.2.

b) 4-Propylcarbamoyl-piperidine-1-caΦoxylic acid tert.-butyl ester (12.34g) is dissolved in dichloromethane (100ml) and trifluoroacetic acid (17.6ml) is added dropwise to the stirred solution over a period of 5 minutes. The mixture is stirred at 20°C for 16 hours, solvents removed by rotary evaporation and the residue partitioned between aqueous sodium hydroxide solution (4M, 180ml) and dichloromethane (200ml). The separated aqueous phase is extracted with further portions (x3) of dichloromethane (200ml) and the combined extracts are dried (MgSO ) and solvent removed by rotary evaporation to afford pure piperidine-4-carboxylic acid propylamide as a white solid. It has 1H and 13C NMR spectra consistent with the claimed structure. [M+H]⁺ = 171.1.

Intermediate 7 - 2-Phenyl-1(S)-pyrrolidin-1-ylmethyl-ethylamine

a) Methanesulfonic acid 2(S)-benzyloxycarbonylamino-3-phenyl-propyl ester (10g) is dissolved in dichloromethane (200ml) and pyrrolidine (23ml) is added. The mixture is stirred for 16 hours at 20°C. Solvent is removed by rotary evaporation and the residue is dissolved in ethanol (200ml) and stirred for 16 hours at 50°C. Solvent is removed by rotary evaporation and the residue is dissolved in dichloromethane (100ml). The solution is washed with portions (2x50ml) of water and brine, dried (MgSO₄) and solvent removed by rotary evaporation. The residue is purified by flash chromatography on a column of silicagel using dichloromethane:ethyl acetate (4:1 , by vol.) as eluant to give (2-phenyl-1(S)-pyrrolidin-1-ylmethyl-ethyl)-carbamic acid benzyl ester.

b) (2-Phenyl-1(S)-pyrrolidin-1-ylmethyl-ethyl)-carbamic acid benzyl ester is dissolved in methanol and catalytically reduced using standard conditions to give 2-phenyl-1(S)-pyrrolidin-1-ylmethyl-ethylamine as an oil.

Intermediate 8 - 1 (S)-Moφhoiin-4-ylmethyl-2-phenyl-ethylamine

a) Methanesulfonic acid 2(S)-benzyloxycaΦonylamino-3-phenyl-propyl ester (10g) is dissolved in dry DMF (100ml) and moφholine (24ml) is added. The mixture is heated at reflux for 30 minutes, the solvent removed by rotary evaporation and the residue purified by flash chromatography on a column of silicagel which is eluted with hexane:ethyl acetate (1:1 , by vol.) to give (1(S)- moφholin-4-ylmethyl-2-phenyl-ethyl)-carbamic acid benzyl ester as a colourless oil. It has a 1H NMR spectrum consistent with the claimed structure.

b) (1 (S)-Moφholin-4-ylmethy!-2-phenyl-ethyl)-carbamic acid benzyl ester (6g) is dissolved in ethanol (150ml) and hydrogenated (1 bar) in the presence of palladium on charcoal (10% w/w, 600mg) for 3 hours at 20°C. Catalyst is removed by filtration and the solvent by rotary evaporation to give 1(S)- moφholin-4-ylmethyl-2-phenyl-ethylamine as a white, waxy solid. It has a 1 H NMR spectrum consistent with the claimed structure. Intermediate 9 -1-(2(S)-Amino-3-phenvl-propvl)-piperidin-4-ol

Analogously as described for Intermediate 8 but starting from 4-hydroxy- piperidine in place of moφholine is prepared 1-(2(S)-amino-3-phenyl-propyl)- piperidin-4-ol as a colourless oil. It has a 1 H NMR spectrum consistent with the claimed structure.

Intermediate 10 - 3(S)-Amino-4-phenyl-butan-1-ol

a) 3-Amino-4-phenyl-butyric acid tert.-butyl ester (1.2g) is dissolved in dry dichloromethane (30ml) and converted by standard procedures to the derivative 3(S)-benzyloxycarbonylamino-4-phenyl-butyric acid tert-butyl ester. It is purified by flash chromatography on a column of silicagel which is eluted with hexane:ethyl acetate (3:1 , by vol.) to give the product as a colourless oil. It has a 1H NMR spectrum consistent with the claimed structure.

b) 3(S)-Benzyloxycarbonylamino-4-phenyl-butyric acid tert.-butyl ester is saponified using standard conditions to give 3(S)-benzyloxycaΦonylamino-4- phenyl-butyric acid as a white solid. It has a 1 H NMR spectrum consistent with the claimed structure.

c) 3(S)-Benzyloxycarbonylamino-4-phenyl-butyric acid (1.7g) is dissolved in dry DME (10ml) and the solution is cooled to -15°C. 4-Methylmoφholine (0.53ml) is added followed by isobutyl chloroformate (0.65ml). The precipitate is removed by filtration and washed with a little DME. A solution of sodium borohydride (0.36g) in water (5ml) is added to the combined cold filtrate and washings followed by water (100ml). The resulting suspension is extracted with portions (3x) of ethyl acetate (25ml) and the combined extracts are dried (MgSO₄) and the residue purified by flash chromatography on a column of silicagel which is eluted with hexane:ethyl acetate (1 :1 , by vol.) to give (1(S)-benzyl-3-hydroxy-propyl)-caΦamic acid benzyl ester as a white solid. It has a 1H NMR spectrum consistent with the claimed structure.

c) (1(S)-Benzy!-3-hydroxy-propyl)-caΦamic acid benzyl ester (1.2g) is dissolved in ethanol (50ml) and hydrogenated (1 bar) in the presence of palladium on charcoal (10% w/w, 150mg) for 2 hours at 20°C. Catalyst is removed by filtration and solvent by rotary evaporation to give 3(S)-amino-4- phenyl-butan-1-ol as a colourless oil. It has a 1 H NMR spectrum consistent with the claimed structure.

Intermediate 11 - (2(S)-BenzyioxycaΦonylamino-3-phenyl-propoxy)-acetic acid

a) (1(S)-Hydroxymethyl-2-phenyl-ethyl)-carbamic acid benzyl ester (10g) is dissolved in dichloromethane (60ml) and bromo-acetic acid tert.-butyl ester (5.7ml) is added with vigorous stirring followed by the addition of aqueous sodium hydroxide (50% w/v, 20ml) and tetrabutylammonium hydrogen sulfate (13g). The mixture is stirred at 20°C for 30 minutes and the suspension washed with water (150ml). The organic phase is dried by rotary evaporation and the residue stirred for 30 minutes in ether (25ml). The suspension is washed with water (15ml), the organic phase is dried (MgSO ) and the residue purified by flash chromatography on a column of silicagel which is eluted with hexane:ethyl acetate (4:1 , by vol.) to give (2(S)- benzyloxycarbonylamino-3-phenyl-propoxy)-acetic acid tert.-butyl ester as a colourless oil. It has a 1 H NMR spectrum consistent with the claimed structure. b) (2(S)-Benzyloxycarbonylamino-3-phenyl-propoxy)-acetic acid tert.-butyl ester (1.9g) is dissolved in methanol (100ml) and saponified with aqueous sodium hydroxide under standard conditions. After work-up, (2(S)- benzyloxycaΦonylamino-3-phenyl-propoxy)-acetic acid is obtained as a white solid on precipitation from alkaline solution by neutralisation (aqeous hydrochloric acid). It has a 1H NMR spectrum consistent with the claimed structure.

Intermediate 12 - (2(S)-Amino-3-phenyl-propoxy)-acetic acid tert.-butyl ester

(2(S)-BenzyloxycaΦonylamino-3-phenyl-propoxy)-acetic acid tert.-butyl ester is catalytically reduced using standard conditions as described for Intermediate 10(c) to give the title compound as a colourless oil. It has a 1 H NMR spectrum consistent with the claimed structure.

Intermediate 13 - 1-(2(S)-BenzyloxycaΦonylamino-3-phenyl-propyl)- piperidine-4-carboxylic acid

a) Methanesulfonic acid 2(S)-benzyloxycaΦonylamino-3-phenyl-propyl ester (22.7g) and piperidine 4-caΦoxylic acid ethyl ester (58.3g) are dissolved in ethanol (150ml) and heated at 70°C for 7 hours. Solvent is removed by rotary evaporation and the residue is purified by flash chromatography on a column of silicagel using dichloromethane:methanol (49:1, by vol.) as eluant to give 1-(2(S)-benzyloxycaΦonylamino-3-phenyl-propyl)-piperidine-4- caΦoxylic acid ethyl ester as a colourless oil. It has 1 H and 13C spectra consistent with the claimed structure.

b) 1-(2(S)-BenzyloxycaΦonylamino-3-phenyl-propyl)-piperidine-4-caΦoxylic acid ethyl ester (17g) is dissolved in ethanol (200ml) and aqueous sodium hydroxide (1M, 200ml) is added. The mixture is stirred at 20°C for 1 hour and aqueous hydrochloric acid (37% w/v, 16.67ml) is added slowly with stirring under ice cooling. Solvents are removed by rotary evaporation and the solid residue is extracted with portions (4 x 150ml) of methanol. The combined extracts are evaporated and the solid suspended in a mixture of acetone

(150ml) and methanol (100ml). After filtration, the filtrate is evaporated to give 1-(2(S)-benzyloxycarbonylamino-3-phenyl-propyl)-piperidine-4-caΦoxylic acid.

Intermediate 14 - [1-(2(S)-Amino-3-phenyl-propyl)-piperidin-4-yl]-moφholin-4- yl-methanone

a) 1-(2(S)-BenzyloxycaΦonylamino-3-phenyl-propyl)-piperidine-4-caΦoxylic acid (1g) is dissolved in dichloromethane (25ml) and 1 ,1-caΦonyl di- imidazole (613mg) is added under an atmosphere of nitrogen. The mixture is stirred at 20°C for 1 hour and moφholine (264mg) is added. The mixture is stirred for 4 hours, solvents are removed by rotary evaporation and the residue is purified by flash chromatography on a column of silicagel using dichloromethane:methanol (99:1 then 49:1, by vol.) as eluant to give [1-(2(S)- benzyloxycarbonylamino-3-phenyl-propyl)-piperidin-4-yl]-moφhoIin-4-yl- methanone. It has 1H and 13C spectra consistent with the claimed structure. [M+H]⁺ = 466.3.

b) [1 -(2(S)- BenzyloxycaΦonylamino-3-phenyl-propyl)-piperidin-4-yl]- moφholin-4-yl-methanone (660mg) is dissolved in methanol (100ml) and hydrogenated (1 bar) in the presence of 10% (w/w) palladium on charcoal (100mg) for 3 hours at 20°C. Catalyst is removed by filtration and the filtrate is evaporated to give [1-(2(S)-amino-3-phenyl-propyl)-piperidin-4-yl]- moφholin-4-yl-methanone. It has a 1 H spectrum consistent with the claimed structure. Intermediate 15 - 2-Phenyt-1(S)-[2-(tetrahydro-pyran-2(RS)-yloxy)- ethoxymethylj-ethylamine

a) 2(S)-Dibenzylamino-3-phenyl-propan-1-ol (2.5g) is dissolved in a suspension of sodium hydride (678mg) in dry DMF (27ml) at 0°C under an atmosphere of nitrogen and 2(RS)-(2-bromo-ethoxy)-tetrahydro-pyran (2.11g) is added slowly. The mixture is heated at reflux for 21 hours, cooled and excess of reagent quenched by the slow addition of water. Solvents are removed by rotary evaporation and the residue is purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (3:17, by vol.) as eluant to give dibenzyl-{2-phenyl-ϊ(S)-[2-(tetrahydro-pyran-2(RS)- yloxy)-ethoxymethyl]-

ethyl}-amine as a colourless oil. It has 1H and 13C NMR spectra consistent with the claimed structure. [M+H]⁺ = 460.1.

b) Dibenzyl-{2-phenyl-1(S)-[2-(tetrahydro-pyran-2(RS)-yloxy)-ethoxymethyl]- ethyl}-amine (490mg) is dissolved in methanol (15ml) and hydrogenated (1 bar) in the presence of 10% (w/w) palladium on charcoal (100mg) for 21 hours at 20°C. Catalyst is removed by filtration and solvent evaporated to give pure 2-phenyl-1 (S)-[2-(tetrahydro-pyran-2(RS)-yloxy)-ethoxymethyl]- ethylamine as a colourless oil. It has has 1H and 13C NMR spectra consistent with the claimed structure. [M+H]⁺ = 279.8.

Intermediate 16 - 2-[4-(2(S)-Amino-3-phenyl-propyl)-piperazin-1-yl]-1- moφholin-4-yl-ethanone

a) Methanesulfonic acid 2(S)-benzyloxycarbonyiamino-3-phenyl-propyl ester (4.53g) is dissolved in ethanol (50ml) and 1-(2-moφholin-4-yl-2-oxo-ethyl)- piperazine (7.98g) is added. The mixture is stirred at 50°C for 4 hours, further amine (4g) is added and the mixture is stirred at 70°C for 18 hours and then heated at reflux for 2 hours. Solvent is removed from the cooled mixture by rotary evaporation and the residue is purified by flash chromatography on a column of silicagel using ethanol:ethyl acetate (3:1, by vol.) as eluant to give {1(S)-[4-(2-moφholin-4-yl-2-oxo-ethyl)-piperazin-1- ylmethyl]-2-phenyl-ethyf}-carbamic acid benzyl ester as a pale yellow foam. It has 1 H and 13C NMR spectra consistent with the claimed structure. [M+H]⁺

= 481.3.

b) {1 (S)-[4-(2-Mθφholin-4-yl-2-oxo-ethyl)-piperazin- 1 -ylmethyl]-2-phenyl- ethyQ-carbamic acid benzyl ester (3.92g) is dissolved in ethanol (50ml) and hydrogenated (1 bar) in the presence of 10^"% (w/w) palladium on charcoal (500mg) for 18 hours at 20°C. Catalyst is removed by filtration and solvent evaporated to give pure 2-[4-(2(S)-amino-3-phenyl-propyl)-piperazine-1-yl]-1- moφhoiin-4-yl-ethanone as a clear oil. It has 1H and 13C NMR spectra consistent with the claimed structure. [M+H]⁺ = 347.1.

Intermediate 17 - 1-(2(S)-Amino-3-phenyl-propyl)-piperidine-4-caΦoxylic acid ethyl ester

a) Methanesulfonic acid 2(S)-benzyloxycaΦonylamino-3-phenyl-propyl ester (22.7g) is dissolved in ethanol (100ml) and piperidine-4-carboxylic acid ethyl ester (58.9g) is added. The mixture is stirred at 70°C for 6 hours, cooled and solvent removed by rotary evaporation. The residue is purified by flash chromatography on a column of silicagel using ethyl acetate: hexane (1:1, by vol.) as eluant to give 1-(2(S)-benzyloxycaΦonylamino-3-phenyl-propyl)- piperidine-4-carboxyiic acid ethyl ester as a yellow oil. It has 1 H and 13C NMR spectra consistent with the claimed structure. [M+H]⁺ = 425.1.

b) 1-(2(S)-BenzyloxycaΦonylamino-3-phenyl-propyl)-piperidine-4-caΦoxylic acid ethyl ester (22.36g) is dissolved in ethanol (100ml) and hydrogenated (1 bar) in the presence of 10% (w/w) palladium on charcoal (3g) for 20 hours at 20°C. Catalyst is removed by filtration and solvent evaporated to give pure 1- (2(S)-amino-3-phenyl-propyl)-piperidine-4-caΦoxylic acid ethyl ester as a yellow oil. It has 1H and 13C NMR spectra consistent with the claimed structure. [M+Hf = 291.2.

Intermediate 18 - 2-[2(S)-Amino-3-(4-methoxy-phenyl)-propoxy]-ethanol

a) [1(S)-Hydroxymethyl-2-(4-methoxy-phenyl)-ethyl]-caΦamic acid tert.-butyl ester (0.85g) and bromo-acetic acid tert.-butyl ester (1.88ml) are dissolved in dichloromethane (10ml) and aqueous sodium hydroxide solution (50% w/v, 20ml) and tetrabutylammonium hydrogen sulfate (1.02ml) are added under vigorous stirring. The mixture is stirred at 20°C for 1 hour. Water (50ml) and ethyl acetate (50ml) are added and the organic phase is separated. The aqueous phase is extracted with ethyl acetate (25ml) and the combined organic phases are washed with portions (50ml) of saturated aqueous sodium bicarbonate and brine, dried (MgSO ) and the solvent removed by rotary evaporation to give [2(S)-tert.-butoxycarbonylamino-3-(4-methoxy- phenyl)-propoxy]-acetic acid tert.-butyl ester which

contains some bromo-acetic acid tert.-butyl ester. This is confirmed by the 1 H NMR spectrum which is consistent with the claimed structure. [M+H]⁺ = 396.2

b) [2(S)-tert.-Butoxycarbonylamino-3-(4-methoxy-phenyl)-propoxy]-acetic acid tert-butyl ester (1.94g) is dissolved in dry THF (20ml) and lithium aluminium hydride (1M in THF, 37.9ml) is added with stirring to the solution at 0°C under an atmosphere of nitrogen. The stirred solution is allowed to warm to room temperature and is stirred for a further hour. Crushed ice is added slowly to destroy excess of reagent, water (100ml) and ethyl acetate (50ml) are added and the organic phase is separated. The aqueous phase is washed with portions (2 x 75ml) of ethyl acetate and the combined organic phases are washed with brine (75ml), dried (MgSO₄) and the solvent removed by rotary evaporation to give the crude product as an oil. This is purified by flash chromatography on a column of silicagel using dichloromethane:methanol (4:1 , by vol.) as eluant to give pure 2-[2(S)-amino-

3-(4-methoxy-phenyl)-propoxy]-ethanol. It has a 1 H spectrum consistent with the claimed structure. [M+CH₅f = 240.0.

The following Examples are synthesised using the Intermediates described and other known compounds.

EXAMPLE 1

a) Method 1 i) 4-(2-Hydroxy-ethyl)-piperidine-1 -caΦoxylic acid tert.-butyl ester (5.15g) is dissolved in fluorotrichloromethane (15ml) and cooled to -78°C in an atmosphere of dry nitrogen. A solution of DAST (3.55ml) in fluorotrichloromethane (15ml) is added and the mixture is stirred with exclusion of moisture for 10 minutes at -78°C and then allowed to warm to room temperature. After a further 30 minutes, the mixture is poured into ice- water (30ml) and the organic phase separated, washed with brine (2x10ml), dried (MgSO4) and the solvent removed by evaporation at reduced pressure to give a residue which is purified by flash chromatography on a column of silicagel using etherhexane (1:1, by vol.) as eluant. Appropriate fractions are combined and the solvent removed to give 4-(2-fluoro-ethyl)-piperidine- 1 -carboxyiic acid tert.-butyl ester.

ii) 4-(2-Fluoro-ethyl)-piperidine-1 -caΦoxylic acid tert-butyl ester (2.2g) is dissolved in saturated hydrogen chloride in acetic acid (12ml) and the solution stirred for 2 hours at 20°C. The solvent is removed by evaporation at reduced pressure and portions of methanol (2x50ml) are evaporated from the residue to give 4-(2-fluoro-ethyl)-pιpeπdιne hydrochloπde which is held in vacuo (NaOH pellets).

Method 2

4-(2-Hydroxy-ethyl)-pipendine-1-carboxylic acid tert.-butyl ester (6.53g) is dissolved in dichloromethane (29ml) and the solution is heated to 80°C at 2 bar (autoclave). Ishikawa reagent (7.29g) dissolved in dichloromethane (8ml) is added over a period of 1 hour under pressure and the mixture is heated for 1.5 hours at 12 bar at 80°C. The cooled mixture is washed with portions (2x20ml) of 50% bπne and 50% bπne buffered to pH4-5. The organic phase is dπed (Na2SO4) and solvent removed by rotary evaporation to give an oil which is purified by flash chromatography on a column of silicagel using hexane:ethyl acetate (10:1 , by vol.) as eluant to give pure 4- (2-fluoro-ethyl)-pιperidine-1-caΦoxylιc acid tert -butyl ester as a light yellow oil. This is converted to 4-(2-fluoro-ethyl)-pιpeπdιne hydrochloride as descπbed in Method 1 above.

Method 3 i) [4-(2-Hydroxy-ethyl)-pιpeπdιn-1-yl]-phenyl-methanone (31.5g) is dissolved in dichloromethane (200ml) and pyπdine (10.9ml) and methanesulfonyl chloπde (11.5ml) are added. The mixture is stirred for 2 hours and the volume reduced to 50ml by evaporation, ethyl acetate (250ml) is added and the solution is washed with portions (250ml) of saturated aqueous sodium bicarbonate and water, the organic phase is dried (MgSO ) and evaporated to give methanesulfonic acid 2-(1-benzoyl-pιperidin-4-yl)-ethy! ester as a waxy solid which is sufficiently pure for use without further purification.

ii) Methanesulfonic acid 2-(1-benzoyl-pιpeπdιn-4-yl)-ethyl ester (41.5g) is dissolved in acetonitπle (150ml), powdered molecular sieve (4 Angstrom) is added followed by TBAF (1M in THF, 145ml) and the mixture is heated at reflux with exclusion of moisture for 2 hours The mixture is cooled, filtered and the filtrate washed with saturated aqueous sodium bicarbonate

(2x200ml) and brine (200ml), dried (MgSO₄) and the solvent evaporated to give an orange oil. Purification by flash chromatography on a column of silicagel using hexane.ether (1 :1 , by vol.) and then ether as eluants gives [4-

(2-fluoro-ethyl)-piperidin-1-yl]-phenyl-methanone as an oil.

iii) [4-(2-Fluoro-ethyl)-piperidin-1-yl]-phenyl-methanone (17.1g) is dissolved in methanol (30ml), aqueous hydrochloric acid (6M, 60ml) is added and the mixture is heated at reflux for 72 hours. Methanol is removed by rotary evaporation and the remaining aqueous solution is washed with ethyl acetate (3x20ml). Solid sodium hydroxide is added to a final pH of 12 and the solution is extracted with ethyl acetate (3x25ml). The combined extracts are dried (MgSO4) ^and evaporated to give 4-(2-fluoro-ethyl)-piperidine as a colourless oil after purification by vacuum distillation, b.p. 45°C/3mm.

b) 2(S)-BenzyloxycaΦonyiamino-3-benzothiazol-2-yl-propionic acid benzyl ester (10g) is dissolved in THF (60ml) and water (20mi), lithium hydroxide monohydrate (1.85g) and aqueous hydrogen peroxide (27.5%, 16ml) are added. The solution is kept at 20°C for 1 hour and sodium sulfite (17g) in water (50ml) is added slowly to the stirred mixture in an ice-bath. The solution is acidified to pH4 (cone, aqueous hydrochloric acid) and extracted with ethyl acetate (2x25ml). The combined organic extracts are washed with brine (50ml), dried (MgSO4) and exaporated to dryness. The residue is triturated with ether (50ml) to afford 2(S)-benzyloxycarbonylamino-3- benzothiazol-2-yl-propionic acid as white crystals which are recrystallised from acetonitrile or tert-butylmethyiether.

c) 4-(2-Fluoro-ethyl)-piperidine hydrochloride (1.27g), 2(S)-benzyloxy- carbonylamino-3-benzothiazol-2-yl-propionic acid (2.70g) and PyBOP (3.93g) are dissolved in dry dichloromethane (100ml) and cooled in an ice- salt bath. Huenig Base (2.44g) is added and the reaction mixture is stirred for 16 hours at 20°C. The solvent is removed by evaporation and the residue dissolved in ethyl acetate, washed with portions (50ml) of cold 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine. The organic phase is dried (MgSO₄), filtered and evaporated to dryness. Chromatography on a column of silicagel, using ethanol:ethyl acetate (1:9, by vol.) as eluant, gives pure 2(S)-benzyloxycaΦonyl-amino-3-benzothiazol- 2-yl-1-[4-(2-fluoro-ethyl)-piperidin-1-yl]-propan-1-one as a pale yellow oil.

d) A solution of 2(S)-benzyloxycaΦonylamino-3-benzothiazol-2-yl-1-[4-(2- fluoro-ethyl)-piperidin-1-yl]-propan-1-one (1.64g) in glacial acetic acid (4.65ml) is stirred with hydrogen bromide in acetic acid (45% w/v, 9.3ml) for 2 hours at 20°C. tert-Butylmethylether (75ml) is added and the mixture is stirred under nitrogen for 18 hours, the crystalline precipitate filtered off and washed with a little tert-butylmethyl ether and triturated with diethyl ether to give pure 2(S)-amino-3-benzothiazol-2-yl-1-[4-(2-fluoro-ethyl)-piperidin-1-yl]- propan-1-one dihydrobromide. (Found C, 41.03; H, 5.13; N, 7.85; F, 3.75. C₁₇H₂2FN₃OS.2HBr requires C, 41.06, H, 4.86; N, 8.45; F, 3.82%).

e) 2(S)-Amino-3-benzothiazol-2-yl-1-[4-(2-fluorchethyl)-piperidin-1-yl]- propan-1-one dihydrobromide (16.4g) is dissolved in water ^"(180ml) and ethyl acetate (90ml) is added. The pH is adjusted to 9 by addition of portions of aqueous sodium hydroxide (4M, ca. 21ml) with vigorous stirring. The organic layer is separated and the aqueous phase is extracted with ethyl acetate (2x100ml). The combined organic extracts are dried ( gSO4) and evaporated to give 2(S)-amino-3-benzothiazol-2-yl-1-[4-(2-fluoro-ethyl)- piperidin-1-yl]-propan-1-one as a pale brown oil.

f) 2(S)-Amino-3-benzothiazol-2-yl-1-[4-(2-fluoro-ethyl)-piperidin-1-yl]-propan- 1-one (13g) and NMM (11.1ml) are dissolved in dichloromethane (125ml) at 0-5°C and a solution of 4-chloro-pyridine-3-sulfonyl chloride (5.5g) is added over a period of 30 minutes with cooling and addition of further NMM to maintain the mixture at pH9. The mixture is stirred at room temperature for

16 hours, filtered and the filtrate dried by rotary evaporation. The residue is dissolved in ethyl acetate (100ml), filtered to remove insoluble material, and the filtrate washed with aqueous acetic acid (10% v/v). The ethyl acetate is removed by rotary evaporation to give a solid which is recrystallised from aqueous ethanol to give 4-chloro-pyridine-3-sulfonic acid {1 (S)-benzothiazol-

2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide as a buff solid m.p. 152°C. [M+H]⁺ = 511.0, 512.8.

g) 4-Chloro-pyridine-3-sulfonic acid {1(S)-benzothiazol-2-ylmethyl-2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide (450mg) and 2(S)-amino-3- phenyl-propan-1-ol (532mg) are dissolved in ethanol (50ml) and the mixture is heated at reflux for 24 hours. After removal of solvent by rotary evaporation, the mixture is purified by flash chromatography on a column of silicagel using ethyl acetate: methanol (9:1, by vol.) as eluant to give 4-(1(S)- hydroxymethyl-2-phenyl-ethylamino)-pyridine-3-sulfonic acid {1(S)- benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide as a white solid. [M+H]⁺ = 626.3.

The following compounds are prepared similarly using appropriate starting materials. Spectral data acquired are consistent with claimed structures.

Example Structure [M+H]⁺ NMR

1a 4-Butylamino-pyridine-3-sulfonic acid {1(S)- 548.3 1H, 13C benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl}-amide

1b 3-Propylamino-pyridine-3-sulfonic acid {1(S)- 533.9 1H, 13C benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl}-amide

c 5-Pentylamino-pyridine-3-sulfonic acid {1(S)- 561.37 1H, 13C benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin- 1 -y l]-2-oxo-ethyl}-amide

d 4-(3-Methyl-butylamino)-pyridine-3-sulfonic 561.75 1 H, 13C acid {1 (S)-benzothiazol-2-ylmethyl-2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

e 4-lsobutylamino-pyridine-3-sulfonic acid 548.2 1 H, 13C

{1(S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro- ethyl)-piperidin- 1 -yl]-2-oxo-ethyl}-amide

f 3-(3-{1(S)-Benzothiazol-2-ytmethyl-2-[4-(2- 592 1H, 13C fluoro-ethyl)-piperidin- 1 -yl]-2-oxo- ethylsulfamoyl}-pyridin-4-ylamino)-propionic acid methyl ester

g 4-[2-(2-Hydroxy-ethoxy)-ethylamino]-pyridine- 580.1 1H, 13C

3-sulfonic acid {1(S)-benzothiazol-2-ylmethyl- 2-[4-(2-fluoro-ethyl)-piperidin-1-yϊ]-2-oxo- ethyl}-amide

h 4-Benzylamino-pyridine-3-sulfonic acid {1(S)- 582 1H, 13C benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin- 1 -yl]-2-oxo-ethyl}-amide

1 i 4-Phenethylamino-pyridine-3-sulfonic acid 596.1 1 H, 13C

{1(S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide

j 4-[2-(4-Methoxy-phenyl)-ethylamino]- 626.1 1 H, 13C pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

k 4-(4-Methyl-benzylamino)-pyridine-3-sulfonic 595.44 1H, 13C acid {1 (S)-benzothiazol-2-ylmethyl-2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

1 4-(2-Amino-phenylamino)-pyridine-3-sulfonic 582.6 1H, 13C acid {1 (S)-benzothiazol-2-ylmethyl-2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

m 4-(4-Pheπyl-butylamino)-pyridine-3-sulfonic 623.75 1H, 13C acid {1 (S)-benzothiazol-2-ylmethy1-2-[4-(2- f luoro-ethyl)-piperidin- 1 -yl]-2-oxo-ethyl}- amide

n 4-[2-(3,4-Dichloro-ρhenyl)-ethylamino]- 664.06r 1 H, 13C pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- 666.06 ylmethyl-2-{4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

1o 4-[(3-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2- 640 1H, 13C fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethylsulfamoyl}-pyridin-4-ylamino)-methyl]- benzoic acid methyl ester

p 4-(2-Amino-benzylamino)-pyridine-3-sulfonic 1 H, 13C acid {1 (S)-benzothiazol-2-ylmethyl-2-[4-(2- fluoro-ethyl)-piperidin- 1 -yl]-2-oxo-ethyl}- amide

q 4-(2-Pyridin-2-yl-ethylamino)-pyridine-3- 596.37 1 H, 13C sulfonic acid {1 (S)-benzothiazo!-2-ylmethyl-2- [4-(2-fluoro-ethyl)-piperidin- -yl]-2-oxo-ethyl}- amide

r 4-[2-(4-Amiπo-phenyl)-ethylamiπo]-pyridine-3- 610.8 1 H, 13C sulfonic acid {1 (S)-benzothiazol-2-ylmethyl-2- [4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

s 4-{2-(4-Hydroxy-phenyl)-ethylamino]-pyridine- 611.8 1 H, 13C

3-sulfqnic acid {1 (S)-benzothiazol-2-ylmethyl- 2-[4-(2-fluoro-ethyl)-piperidin- 1 -y l]-2-oxo- ethyQ-amide

1 4-(1 (S)-Hydroxymethyl-pentylamino)-pyridine-

3-sulfonic acid {1 (S)-benzothiazol-2-ylmethyl- 2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethyl}-amide

1u 4-(1 (R)-Hydroxymethyl-pentylamino)- 591.8 pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl)-amide 12-(3- 1(S)-Benzothiazol-2-ylmethyl-2-[4-(2- 690 1 H, 13C fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethylsulfamoyl}-pyridin-4-ylamino)- v dodecanoic acid

w 4-(3,4-Dimethoxy-phenylamino)-pyridine-3- 628 1 H, 13C sulfonic acid {1 (S)-benzothiazol-2-ylmethyl-2- [4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

x 4-[2-(2-Amino-phenyl)-ethylamino3-pyridine-3- 610.1 1 H, 13C sulfonic acid {1 (S)-benzothiazol-2-ylmethyl-2- [4-(2-fIuoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

y 4-[2-(3a,7a-Dihydro-1H-indol-3-yl)-1(S)- 665.4 hydroxymethyl-ethylamino]-pyridine-3- sulfonic acid {1 (S)-benzothiazol-2-ylmethyl-2- [4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

z 4-[2-(3a,7a-Dihydro-1H-indol-3-yl)-1 (R)- 665.3 hydroxymethyl-ethylamino]-pyridine-3- sulf onic acid {1 (S)-benzothiazol-2-ylmethyl-2- [4-(2-fluoro-ethyl)-piperidin- 1 -yl]-2-oxo-ethy(}- amide

aa 4-(1(S)-Hydroxymethyl-2-pyridin-3-yl- 626.8 1H, 13C ethylamino)-pyridine-3-sulfonic acid (1(S)- benzothiazol-2-ylmethyl-2-[4-(2-ftuoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl}-amide

ab 4-[1 (S)-Hydroxymethyl-2-(4-nitro-phenyl)- 671.2 1 H, 13C ethytamino]-pyridine-3-sulfoπic acid (1(S)- benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl)-amide

ac 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 627.9 pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperazin-1-yl]- 2-oxo-ethyl}-amide

ad 4-(2-Cyclohexyl-1(S)-hydroxy methyl- 632.4 1 H, 13C ethylamino)-pyridine-3-sulfonic acid {1(S)- beπzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl}-amide

ae 4-(2-t/aπs-Phenyl-cyclopropylamino)- 608.6 1 H, 13C pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

af 4-(1(S)-Hydroxymethyl-3-methylsulfanyl- 610.6 1 H, 13C propylamino)-pyridine-3-sulfonic acid (1(S)- benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oχo-ethyr>-amide

lag 4-(1 (S)-Methoxymethyl-2-phenyl-ethylamiπo)- 640.5 pyridine-

3-sulfonic acid {1 (S)-benzothiazol-2-ylmethyl- 2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethyl}-amιde

ah 4-(5-Hydroxy-pentylamιno)-pyπdιne-3- 579 1 H, 13C sulfonic aαd {1 (S)-benzothιazol-2-ylmethyl-2- [4-(2-fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-ethy(}- amide

aι 4-(4-Dιmethylamιno-phenylamιno)-pyπdιne-3- 611 4 1H, 13C sulfonic acid {1 (S)-benzothιazol-2-ylmethyl-2- [4-(2-fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-ethyl}- amide

aj 4-(1(R)-Methyl-2-phenyl-ethylamιno)-pyπdιne- 610 7 1H

3-sulfonιc acid {1 (S)-benzothιazol-2-ylmethyl- 2-[4-(2-fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo- ethyl}-amιde

ak 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamιno)- 624 4 pyπdιne-3-sulfonιc aαd {1 (S)-benzothιazol-2- ylmethyl-2-[4-(2-hydroxy-ethyl)-pιpeπdιn-1-yl]- 2-oxo-ethyl]-amιde

al 4-(2-frans-Phenyl-cyclopropylamιno)- 609 6 1H, 13C pyπdιne-3-sulfoπιc acid {1 (S)-benzothιazol-2- ylmethyl-2-[4-(2-fIuoro-ethyl)-pιperazιn-1-y!]- 2-oxo-ethyl}-amιde

am 4-(2-Hydroxy-phenylamιno)-pyπdιne-3- 584 2 1 H, 13C sulfonic acid {1 (S)-benzothιazol-2-ylmethyl-2- [4-(2-fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-ethyl>- amide an 4-(2-Methyisulfanyl-phenylamino)-pyridine-3- 614.2 1 H, 13C sulfonic acid {1 (S)-benzothiazoi-2-ylmethyl-2- [4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

ao 4-{2-Phenyl-1(S)-[2-(tetrahydro-pyran-2(RS)- 755.2 yloxy)-ethoxymethyl]-ethylamino}-pyridine-3- sulfonic acid {1 (S)-benzothiazol-2-ylmethyl-2- [4-(2-fIuoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

ap 4-(2-rraπs-Phenyl-cyciopropylamino)- 606 pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]- 2-oxo-ethyl}-amide

aq 4-(2-Cyclohexyl-1(S)-hydroxymethyl- 630.6 ethylamino)-pyridine-3-sulfonic acid (1 (S)- benzothiazol-2-ylmethyl-2-[4-(2-hydrόxy- ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide

ar 4-(1 (R)-Hydroxymethyl-2-phenyl-ethylamino)- 1H, 13C pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethy l)-piperidin- 1 -yl]-2- oxo-ethyl}-amide

1as 4-(1 (S)-Hydroxymethyl-propylamino)- 564.4 pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide at 4-{2-Phenyl-1(S)-[2-(tetrahydro-ρyran-2(RS)- 752.3 1 H, 13C yloxy)-ethoxymethyl]-ethylamιno}-pyπdιne-3- sulfonic aαd {1 (S)-benzothιazol-2-ylmethyl-2- [4-(2-hydroxy-ethy l)-pιpeπdin- 1 -y l]-2-oxo- ethyl}-amιde

au 4-(1 (R)-Hydroxymethyl-2-phenyl-ethylamιno)- 627 4 pyπdιne-3-sulfonιc acid {1(S)-benzothιazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-pιperazιn-1-yl]- 2-oxo-ethyl}-amιde

1av 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamιno)- 642.1 , pyπdιne-3-sulfonιc acid {1 (S)-benzothιazol-2- 644 0 ylmethyl-2-[4-(2-chloro-ethyl)-pιpendιn- 1 -yl]- 2-oxo-ethyl}-amιde

law 4-(1 (S)-Chloromethyl-2-phenyl-ethylamιno)- 644.2, 1 H, 13C pyπdιne-3-sulfonιc acid {1 (S)-benzothιazol-2- 646.2 ylmethyl-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1-yl]-2- oxo-ethyl}-amιde

1ax 4-[1(S)-Hydroxymethyl-2-(4-hydroxy-phenyl)- 642.3 1 H, 13C ethylamιno]-pyπdine-3-sulfonιc acid (1(S)- benzothιazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- pιpeπdιn-1-yl]-2-oxo-ethyl}-amιde

lay 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamιno)- 625 3 1 H, 13C pyπdιne-3-sulfontc acid {1 (S)-benzothιazol-2- ylmethyl-2-[4-(2-hydroxy-ethyl)-pιperazιn-1- yl]-2-oxo-ethyl}-amιde az 4-(1(S)-Hydroxymethyl-2-pheny!-ethylamιno)- 619.4 1H, 13C pyndιne-3-sulfonιc aαd {2-[4-(2-fluoro-ethyl)- pιpeπdιn-1-yl]-1(S)-naphthalen-2-ylmethyl-2- oxo-ethyl}-amιde

ba 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamιno)- 570.2 1 H, 13C pyndιne-3-sulfonιc acid {2-[4-(2-fluoro-ethyl)- pιpeπdιn-1-yl]-2-oxo-1(S)-pyπdιn-3-ylmethyl- ethyfj-amide

bb 4-[1(S)-Hydroxymethyl-2-(4-hydroxy-ρhenyl)- 635 ethylamιno]-pyπdιne-3-sulfonιc acid {2-[4-(2- fluoro-ethyl)-pιpeπdιn-1-yl]-1(S)-naphthalen- 2-ylmethyl-2-oxo-ethyl}-amιde

bc 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamιno)- 569 4 pyridιne-3-sulfonιc aαd_{1 (S)-benzyl-2-[4-(2- fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-ethyl}- amide

bd 4-(1(S)-Hydroxymethyl-2-phenyl-ethyiamιno)- 570 4 1 H, 13C pyndϊhe-3-sulfonιc acid (2-[4-(2-fluoro-ethyl)- pιpeπdιn-1-yl]-2-oxo-1 (S)-pyπdιn-2-ylmethyl- ethyfj-amide

1be 3(S)-(3-{1 (S)-Benzothιazol-2-ylmethyl-2-[4-(2- 710 5 1 H, 13C fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo- ethylsulfamoyl}-pyndιn-4-ylamιno)-4-phenyl- butyπc acid tert -butyl ester bf 4-(1 (S)-Hydroxymethyl-2-ρhenyl-ethylamino)- 571.4 1 H, 13C pyridine-3-sulfonic acid {2-[4-(2-fluoro-ethyl)- piperazin-1-yl]-2-oxo-1(S)-pyridin-2-ylmethyl- ethy(}-amide

bg 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 570.3 1 H, 13C pyridine- 3-sulfonic acid (2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-1(S)-pyridin-4-ylmethyl- ethyrj-amide

bh 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 599.2 1 H, 13C pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-1(S)-(4-methoxy-benzyl)-2-αxo- ethyl]-amide

bi 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 575.5 1 H, 13C pyridine-3-sulfonic acid {1 (S)- cydohexylmethyl-2-[4-(2-fluoro-ethyl)- pιperidirv-1-yl]-2-oxo-ethyl>-amide

bj 4-[1(S)-Hydroxymethyl-2-(4-methoxy-phenyl)- 599.4 1 H, 13C ethylamino)-pyridine-3-sulfonic acid {1(S)-[4- (2-fluoro-ethyl)-piperidine-1-caΦonyl]-2- phenyl-ethyl}-amide.

bk 4-[1(S)-Hydroxymethyl-2-(4-methoxy-phenyl)- 656.3 1 H, 13C ethylamino]-pyridine-3-sulfonic acid {1(S)- benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl}-amide

bl 4-[1 (S)-Hydroxymethyl-2-(4-methoxy-pheπyl)- 600.4 1 H, 13C ethylamιno]-pyπdιne-3-sulfonιc aαd (2-[4-(2- fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-1(R)- pyπdin-2-ylmethyl-ethyl}-amιde

bm 4-[1 (S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 613 5 1 H, 13C ethylamιno]-pyπdιne-3-sulfoπιc acid {1(S)-[4- (2-fluoro-ethyl)-pιpeπdιne-1-carbonyl]-2- phenyl-ethyl}-amιde

bn 4-{1 (S)-Hydroxymethyl-2-(4-methoxy-phenyl)- 629 4 1 H, 13C ethylamιno]-pyπdιne-3-sulfonιc acid [1(S)-[4- (2-fluoro-ethyl)-pιpeπdιne-1-caΦonyl]-2-(4- methoxy-phenyl)-ethyl]-amιde

bo 4-[1 (S)-Hydroxymethyl-2-(4-methoxy-pheny I)- 600 4 1 H , 13C ethy!amιno]-pyπdιne-3-sulfonιc aαd {2-[4-(2- fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-1(S)- pyπdιn-2-ylmethyl-ethyl}-amιde

bρ 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 614 4 1 H ethylamιno]-pyndιne-3-sulfonιc aαd {1(S)-[4- (2-fluoro-ethyl)-pιpeπdιne-1-caΦonyl]-2- pyπdιn-2-yl-ethyl}-amιde

bq 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 643 4 1 H ethylamιno]-pyπdιne-3-sulfonιc acid [1(S)-[4- (2 fluoro-ethyl)-pιpeπdιne-1-caΦonyl]-2-(4- methoxy-phenyl)-ethyl]-amιde

1br 4-(1(R)-Methyl-2-phenyl-ethylamιno)-pyπdιne- 553 4 1 H, 13C

3-sulfonιc acid (1 (S)-[4-(2-fluoro-ethyl)- piperidine-1-caΦonyl]-2-phenyl-ethyl}-amide

bs 4-(1 (S)-Hydroxymethyl-2-phenyl-ethyiamino)- 612.9 1H pyridine-3-sulfonic acid {1 (S)-(4-ethoxy- benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

bt 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 614.4 1H, 13C pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-1(S)-(4-nitro-benzyl)-2-oxo- ethyl]-amide

bu 4-(2-Cyclohexyl-1(S)-hydroxymethyl- 576.4 1 H, 13C ethylamino)-pyridine-3-sulfonic acid {2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-1(S)- pyridin-2-ylmethyl-ethyl}-amide

bv 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 586.2 1 H pyridine-3-sulfonic acid {2-[4-(2-chloro-ethyl)- piperidin-1-yl]-2-oxo-1(S -pyridin-2-ylmethyi- ethyl)-amide

bw 4-(1(R)-Methyl-2-phenyl-ethylamino)-pyridine- 554.5 1 H, 13C

3-sulfonic acid {1 (S)-[4-(2-fluoro-ethyl)- piperidine-1-caΦonyl]-2-pyridin-2-yl-ethyl}- amide

bx 4-[2-(4-Ethoxy-phenyl)-1(S)-hydroxymethyl- 613.3 1H, 13C ethylamino]-pyridine-3-sulfonic acid {1 (S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide by 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 576.2 1 H, 13C pyridine-3-sulfonic add {2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-1(S)-thiazol-4-ylmethyl- ethyl)-amide

bz 4-(2-Benzylsulfanyl-1(R)-hydroxymethyl- 615.2 1H, 13C ethylamino)-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

ca 4-(1 (S)-Hydroxymethyl-3-phenyl- 583.3 1 H, 13C propylamino)-pyridine-3-sulfonic add {2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-1(S)- pyridin-2-ylmethyl-ethyl}-amide

cb 4-[2-(4-Ethoxy-phenyl)-1(S)-hydroxymethyl- 614.4 1 H, 13C ethylamino]-pyridine-3-sulfonic acid {2-[4-(2- fluoro-ethyl)-piperidin-1-ylj-2-oxo-1(R)- pyridin-2-ylmethyl-ethyl}-amide

cc 4-[2-(4-Ethoxy-phenyl)-1 (S)-hydroxymethyl- 614.4 1 H, 13C ethylaminol-pyridine^-sulfonic acid {2-[4-{2- fluoro-ethyl)-piperidin-1 -yl]-2-oxo-1 (S)- pyridin-2-ylmethyl-ethyi}-amide

1cd 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 587.3 1 H, 13C pyridine-3-sulfonic acid {1 (S)-(4-fluoro- benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyi}-amide ce 4-(1(S)-Hydroxymethyl-3-phenyl- 584.4 1 H, 13C propylamino)-pyridine-3-sulfonic acid {2-[4-(2- fluoro-ethyl)-piperidin-1 -yl]-2-oxo-1 (S)- pyridin-2-yimethyl-ethy(}-amide

cf 4-(1(S)-Hydroxymethyl-3-phenyl- 584.3 1H, 13C propylamino)-pyridine-3-sulfonic acid {2-(4-(2- fluoro-ethyl)-piperidin-1 -yl]-2-oxo-1 (R)- pyridin-2-ylmethyl-ethyl}-amide

cg 4-(2-Benzylsulfanyl-1(R)-hydroxymethyl- 616.4 1H, 13C ethylamino)-pyridine-3-sulfonιc acid (2-[4-(2- fluoro-ethyl)-piperidin-1 -yl]-2-oxo-1 (S)- pyridin-2-ylmethyl-ethyr>-amide

ch 4-(2-Benzylsulfanyl-1(R)-hydroxymethyl- 616.3 1 H, 13C ethylamino)-pyridine-3-sulfonic acid {2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-1(R)- pyridin-2-yimethyl-ethyl}-amide

ci 4-[2-(4-Fluoro-phenyl)-1(S)-hydroxymethyl- 587.2 1H, 13C ethylamino]-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

cj 4-(1(S)-Hydroxymethyl-2-ρhenyl-ethylamino)- 610.2 1 H, 13C pyridine-3-sulfonic acid {1 (S)-benzooxazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyfj-amide

1ck 4-[2-(4-Fluoro-phenyl)-1(S)-hydroxymethyl- 588.2 1 H, 13C ethylamino]-pyridine-3-sulfoπic add {2-[4-(2- fluoro-ethyl)-piperidin-1 -yl]-2-oxo- 1 (S)- pyridin-2-ylmethyl-ethyI}-amide

cl 4-[2-(4-Methoxy-phenyl)-1(R)-methyl- 613.3 1H, 13C ethylamino]-pyridine-3-sulfonic acid [2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-1(S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amide

cm 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 612.3 1H, 13C pyridine-3-sulfonic acid {1 (S)-(4- dimethylamino-benzyi)-2-[4-(2-fluoro-ethyl)- piperidin- 1 -yl]-2-oxo-ethy(}-amide

cn 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 629.3 1H, 13C pyridine-3-sulfonic acid {1 (S)-(3,4-dimethoxy- benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

co 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 613.2 1H, 13C pyridine-3-sulfonic acid (1(S)- benzo[1 ,3]dioxol-5-ylmethyl-2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-2-ox -ethyl}-amide

cp 4-(1(S)-Hydroxymethyl-2-ρhenyl-ethylamino)- 630.2 1H, 13C pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-1(S)-(4-hydroxy-3-nitro- benzyl)-2-oxo-ethyl]-amide

1cq 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 585.1; 1H, 13C pyridine-3-sulfonic acid {1 (S)-benzyl-2-[4-(2- 586.9 chloro-ethy -piperidin- 1 -yl]-2-oxo-ethyl}- amide

cr 4-[2-(3,4-Dimethoxy-phenyl)-1(S)- 629.3 1 H hydroxymethyl-ethyiamino]-pyridine-3- sulfonic add {1 (S)-benzy!-2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-2-oxo-ethyr}-amide

cs 4-[1(S)-Hydroxymethyl-2-(4-methoxy-phenyl)- 617.3 1 H, 13C ethylamino]-pyridine-3-sulfonic acid {1 (S)-(4- fluoro-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin- 1 -yl]-2-oxo-ethyl}-amide

ct 4-(1(S)-Benzyl-2-[4-(2-moφholin-4-yl-2-oxo- 764.5 1 H, 13C ethyl)-piperazin-1-yl]-ethylamino}-pyridine-3- sulfonic add {1(S)-benzyl-2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide

cu 4-[2-(3,4-Dimethoxy-phenyl)-ΗS)- 647.3 1 H, 13C hydroxymethyl-ethylamino]-pyridine-3- sulfonic acid {1 (S)-(4-fluoro-benzyl)-2-[4-(2- f!uoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl>- amide

cv 4-[2-(3,4-Dimethoxy-ρhenyl)-1(S)- 658.8 1 H, 13C hydroxymethyl-ethylamino]-pyridine-3- sulfonic acid [2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-1(S)-(4-methoxy-benzyl)-2-oxo-ethyl]- amide

1cw 4-[1 (S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 631 1H, 13C ethylamino]-pyridine-3-sulfonic acid {1 (S)-(4- fluoro-benzyl)-2-(4-(2-fluoro-ethyl)-piperidin-

1 -y l]-2-oxo-ethy l}-amide

cx 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 659.29 1 H, 13C ethylamino]-pyridine-3-sulfonic acid [2-[4-(2- chloro-ethyl)-piperidin- 1 -yl]- 1 (S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amide

cy 4-[1 (S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 625.4 1 H, 13C ethylamino]-pyridine-3-sulfonic acid [2-(4- ethyl-piperidin-1-yl)-1(S)-(4-methoxy-benzyi)- 2-oxo-ethyl]-amide

1cz 4-[1 (S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 629.25 1 H, 13C ethylamino]-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-chloro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

Ida 4-^1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 614.3 1 H, 13C pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyr)- piperidin-1 -yl]-1 (S)-(4-nitro-benzyl)-2-oxo- ethyl]-amide

1db 4-(1 (S)-Hydroxymethyi-3-methylsulfanyl- 553.5 1H, 13C propylamino)-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

1dc 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 551.4 1 H, 13C pyridine-3-sulfonic acid [1(S)-benzyl-2-(4- ethyl-piperidin-1-yl)-2-oxo-ethyl]-amide

dd 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 536.9 1 H, 13C pyridine-3-sulfonic add [1 (S)-benzyl-2-(4- methyl-piperidin-1-yl)-2-oxo-ethyl]-amide

de 4-Ethylamino-pyridine-3-suifonic acid [1(S)- 444.9 1H, 13C benzyl-2-(4-ethyl-piperidin-1-yl)-2-oxo-ethyl]- amide

df 4-Amino-pyridine-3-sulfonic acid [1 (S)- 417 1 H, 13C benzyl-2-(4- ethyl-piperidin-1-yl)-2-oxo-ethyl]-amide

dg 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 570.7 1 H, 13C pyridine-3-sulfonic acid [1(S)-benzyl-2-(3,4- dihydro-1.H.-isoquinolin-2-yl)-2-oxo-ethyl]- amide

dh 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 630.7 1 H, 13C pyridine-3-sulfonic acid [1(S)-benzyl-2-(6,7- dimethoxy-3,4-dihydro-1.H.-isoquinolin-2-yl)- 2-oxo-ethyt]-amide

di 4-[1 (S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 670.8 1 H, 13C ethylamino]-pyridine-3-sulfonic acid (1(S)- benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1 -yl]-2-oxo-ethyl}-amide

dj 4-[1 (S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 668.4 1 H, 13C ethylamino]-pyridine-3-sulfonic acid (1(S)- benzothiazol-2-ylmethyl-2-[4-(2-hydroxy- ethyi)-piperidin-1-yl]-2-oxo-ethyl}-amide

dk 4-[(3- 1(S)-Benzothiazol-2-ylmethyl-2-[4-(2- 625.56 1 H, 13C fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethylsulfamoyl)-pyridin-4-ylamino)-methyl]- benzoic acid

dl 4-Pentylamino-pyridine-3-sulfonic acid (1 (S)- 559.37 1 H, 13C benzothiazol-2-ylmethyl-2-{4-(2-hydroxy- ethyl)-piperidin- 1 -y l]-2-oxo-ethyl} amide

dm 4-Phenethylamino-pyridine-3-sulfonic acid 593.75 1 H, 13C

{1(S)-benzothiazoi-2-ylmethyl-2-[4-(2- hydroxy-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

dn 3(S)-(3-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2- 654.4 1 H, 13C fluoro-ethyf)-piperidin-1-yl]-2-oxo- ethylsulfamoyl)-pyridin-4-ylamino)-4-phenyl- butyric acid

do 3(S)-(3-{1 (S)-Benzyl-2-[4-(2-fluoro-ethyl)- 597.19 1H piperidin-1-yl]-2-oxo-ethylsulfamoyl}-pyridin- 4-ylamino)-4-phenyl-butyric acid

1dp 4-(1(S)-Benzyl-3-hydroxy-propylamino)- 640.3 pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide 1dq 4-[2-(4-Amino-phenyl)-1 (S)-hydroxymethyl- 641.6 1 H, 13C ethylamino]-pyridine-3-sulfonic acid (1(S)- benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1 -yl]-2-oxo-ethyl}-amide

Examples 1 di and 1dj are obtained by acidic deprotection of Examples 1ao and 1at using standard conditions.

Examples 1dk and 1dn are obtained by alkaline deprotection of Examples 1o and 1 be; 1dl and 1dm from the corresponding O-acetyl esters; and 1do from the corresponding methyl ester, using standard conditions.

Example 1dp is obtained by the action of borane:THF complex on Example

1dn.

Examples 1t and 1 u, also 1y and 1z, are obtained by silicagel column chromatographic separation of diastereomeric mixtures resulting from reaction with racemic amines. In both cases, tentative stereochemical assignments are made on the bases of (i) the relative potencies of the pairs of compounds and (ii) their relative elution times on hplc analysis, by analogy with other diastereomeric pairs of known absolute configuration.

Examples 1 bl and 1bo are tentatively assigned their stereochemistries by analogy of their potencies and chromatographic behaviours to diastereomeric pairs of known absolute configuration.

Example 1dq is obtained by catalytic reduction of Example 1ab

Examples 1cb and 1cc, 1ce and 1cf, and 1cg and 1ch are isolated by silicagel column chromatography of diastereomeric mixtures.

EXAMPLE 2

a) Analogously as described for Example 1(c) but using 3-(4-benzyloxy- phenyl)-2(S)-tert.-butoxycaΦonylamino-propionic acid in place of 2(S)- benzyloxycarbonylamino-3-benzothiazol-2-yl-propionic acid and 4-(2-chloro- ethyl)-piperidine in place of 4-(2-fluoro-ethyl)-piperidine is prepared {2-(4- benzyloxy-phenyl)-1 (SH4-(2-chloro-ethyl)-pιperidine-1-caΦonyl]-ethyl}- caΦamic add tert.-butyl ester.

b) {2-(4-Beπzyloxy-phenyl)-1(S)-[4-(2-chloro-ethyl)-pιpeπdine-1-cart5onyl]- ethyQ-carbamic add tert.-butyl ester (1.84g) is dissolved in a solution of hydrogen chloπde in ethanol (5.6M, 20ml) and the mixture is stirred at room temperature for 1 hour. Solvents are removed by rotary evaporation and toluene (25ml) is evaporated from the residue The resulting foam is kept in vacuo over solid sodium hydroxide (pellets) for 2 hours to give 2(S)-amιno-3- (4-benzyloxy-phenyl)-1-[4-(2-chioro-ethyl)-pιpeπdιn-1-yl]-propan-1-one hydrochloride.

c) Analogously as descπbed for Example 1 (f-g) but using 2(S)-amιno-3-(4- benzyloxy-phenyl)- 1 -{4-(2-chloro-ethyi)-pιpeπdin-1 -yl]-propan- 1 -one hydrochloride in place of 2(S)-amιno-3-benzothiazol-2-yl-1-[4-(2-fluoro-ethyl)- pιperidin-1-yl]-propan-1-one dihydrobromide is prepared 4-(1(S)- hydroxymethyl-2-phenyl-ethylamιno)-pyπdιne-3-sulfonιc aαd {1 (S)-(4- benzyloxy-benzyl)-2-(4-(2-chloro-ethyl)-pιpeπdin-1-yi]-2-oxo-etJιyl)-arrMde

d) 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamιno)-pyπdιπe-3-sulfonιc acid {1(S)-(4-benzyloxy-benzyl)-2-[4-(2-chloro-ethyl)-pιpendιn-1-yl]-2-oxo-ethyl}- amide (0.184g) is dissolved in methanol (20ml) and hydrogenated (1 bar, 20°C, 24 hours) in the presence of 10% palladium on charcoal (100mg). After removal of catalyst by filtration and of the solvent by rotary evaporation, 4-(1 (S)-hydroxymethyl-2-phenyl-ethylamιno)-pyπdιne-3-sulfonιc acid [2-[4-(2- chloro-ethyl)-pιpeπdιn-1-yl]-1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]-amιde is obtained as a white foam. [M+H]⁺ = 601.3, 603 2. The following compounds are prepared similarly:

Example Structure [M+H]⁺ NMR

2a 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylarnino)- 585.3 1 H, 13C pyridine-3-sulfonic acid [2-[4-{2-fluoro-ethyl)- piperidin-1-yl]-1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

2b 4-[1 (S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 629.3 1 H ethylamino]-pyridine-3-sulfonic acid [1(S)-[4-(2- fluoro-ethyl)-piperidine-1-caΦonyl]-2-(4-hydroxy- phenyl)-ethyl]-amide

2c 4-[1 (S)-Hydroxymethyl-2-(4-methoxy-phenyl)- 615.4 1H, 13C ethylamino]-pyridine-3-sulfonic acid [2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-1(S)-(4-hydroxy-benzyl)-2-oxo- ethyl]-amide

2d 4-(2-Cyclohexyl-1 (S)-hydroxymethyl-ethylamino)- 591.5 1 H, 13C pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin-1-yl]- (S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

2e 4-(1 (R)-Methyl-2-phenyl-ethylamino)-pyridine-3- 569.3 1 H, 13C sulfonic acid [2-[4-(2-fluoro-ethyl)-piperidin-1-yl]- 1 (S)-(4-hydroxy-benzyl)-2-oxo-ethyl]-amide

2f 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 583.4 1 H, 13C pyridine-3-sulfonic acid {1(S)-(4-hydroxy-benzyl)-2- [4-(2-hydroxy-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

g 4-[2-(4-Methoxy-phenyl)-1 (RS)-methyl-ethylamino]- 599.3 1 H, 130 pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin- 1 -yl]- 1 (S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

h 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 645.2 1 H ethylamino]-pyridine-3-sulfonic acid [2-[4-(2-chloro- ethyl)-piperidin-1-yl]-1(S)-(4-hydroxy-benzyl)-2-oxo- ethyl]-amide

i 4-[1 (S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 627.4 1 H ethylamino]-pyridine-3-sulfonic acid [1(S)-[4-(2- hydroxy-ethyl)-piperidine-1-caΦonyl]-2-(4-hydroxy- phenyl)-ethyl]-amide

j 4-[2-(4-Methoxy-phenyl)-1 (R)-methyl-ethylaminoj- 599.3 1 H, 130 pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin- 1 -yl]- 1 (S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- a ide

k 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)- 601.3 1 H, 130 pyridine-3-sulfonic acid {1 (S)-(3,4-dihydroxy- benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethyl}-amide

I 4-(1 (S)-Hydroxymethyl-2-ρhenyl-ethylamino)- 567.3 1 H, 130 pyridine-3-sulfonic acid [2-(4-ethyl-piperidin-1-yl)- 1 (S)-(4-hydroxy-benzyl)-2-oxo-ethyl]-amide m 4-[2-(3,4-Dimethoxy-phenyl)-1(S)-hydroxymethyl- 645.5 1 H, 130 ethylamino]-pyridine-3-sulfonic acid [2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-1(S)-(4-hydroxy-beπzyl)-2-oxo- ethyl]-amide

n 4-[2-(3,4-Dimethoxy-phenyl)-1(S)-hydroxymethyt- 627.4 1H, 130 ethylamino]-pyridine-3-sulfonic acid [2-(4-ethyl- piperidin-1-yl)-1 (S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

o 4-(1(SHBis-(2-methoxy-ethyl)-amino]-methyl}-2- 700.29 phenyl-ethylamino)-pyridine-3-sulfonic acid [2-[4- (2-fluoro-ethyl)-piperidin-1 -yl]-1 (S)-(4-hydroxy- benzyl)-2-oxo-ethyl]-amide

p 4-[1 (S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 611.27 1H, 130 ethylamino]-pyridine-3-sulfonic acid [2-(4-ethyl- piperidin-1-yl)-1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

q 4-(2-trans-Phenyl-cyciopropytamino)-pyridine-3- 566.6 1 H, 130 sulfonic acid [2-[4-(2-fluoro-ethyl)-piperidin-1-yl]- 1 (S)-(4-hydroxy-benzyl)-2-oxo-ethyl]-amide

r 4-(1(S)-Hydroxymethyl-3-methylsulfanyl- 550.7 1 H, 130 propylamino)-pyridine-3-sulfonic acid [2-(4-ethyl- piperidin-1-yl)-1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide EXAMPLE 3

a) Analogously as described for Example 1(c) but using 2(S)-tert- butoxycarbonylamino-3-pyridin-2-yl-propionic acid in place of 2(S)- benzytoxycaΦonylamino-3-benzothiazol-2-yl-propionic add is prepared {2-(4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-1(S)-pyridin-2-ylmethyl-ethyl>- caΦamic add tert-butyl ester. This is treated as described for Example 2(b) to give 2(S)-amino-1-[4-(2-fluoro-ethyl)-piperidin-1-yl]-3-.pyridin-2-yl- propan-1-one hydrochloride. This is treated as described for Example 1(f) to give 4-chloro-pyridine-3-sulfonic acid (2-[4-(2-fIuoro-ethyl)- piperidin-1-yl]-2-oxo-1 (S)-pyridin-2-ylmethyl-ethyl}-arnide.

b) 2(S)-Amino-3-(3,4-dimethoxy-phenyl)-propan-1-ol (57mg), Huenig Base (120μl) and 4-chloro-pyridine-3-sulfonic acid {2-[4-(2-fluoro-ethyi)- piperidin-1-yl]-2-oxo-1(S)-pyridin-2-ylmethyl-ethyl}-amide (75mg) are dissolved in ethanol (5ml) and heated in a sealed vial at 90°C for 72 hours. The solvent is removed by rotary evaporation and the residue is purified by flash-chromatography on a column of silicagel using chloroform: methanol (19:1 , by vol.) as eluant to give 4-[2-(3,4-dimethoxy- phenyl)-1 (S)-hydroxymethyl-ethylamino]-pyridine-3-sulfonic acid {2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-1(S)-pyridin-2-ylmethyl-ethyl}-amide. [M+H]⁺ = 630.3.

EXAMPLE 4

a) Analogously as described for Examples 1(c) and 2(b) but using 4- ethyl-piperidine and 2(S)-tert.-butoxycarbonylamino-3-(4-nitro-phenyl)- propionic acid in place of 4-(2-fluoro-ethyl)-piperidine hydrochloride and 2(S)-benzyloxy-caΦonylamiπo-3-benzothiazol-2-yl-propionic acid is prepared 2(S)-amino-1-(4-ethyl-piperidin-1-yl)-3-(4-nitro-phenyl)-propan- 1-one hydrochloride. b) 2(S)-Amino-1-(4-ethyl-piperidin-1-yl)-3-(4-nitro-phenyl)-propan-1-one hydrochloride (9.2g) and Huenig Base (5.77ml) are dissolved in dichloromethane (80ml) and 4-chloro-pyridine-3-sulfonyl chloride (7.03g) is added to the solution which is stirred for 24 hours at room temperature. Water (100ml) and brine (100ml) are added, the organic phase is separated and the aqueous solution is extracted with dichloromethane (3x100ml). The combined extracts are dried (MgSO4) and the solvent evaporated to give a brown waxy solid which is purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (19:1 , folfowed by 3:2, by vol.) as eluant to give 4-chloro-pyridine-3- sulfonic acid [2-(4-ethyl-piperidin-1-yl)-1(S)-(4-nitro-benzyl)-2-oxo-ethyl]- amide. [M+H]⁺ = 480.9, 482.7.

c) (i) 2(S)-Dibenzylamino-3-phenyl-propan-1-ol (2g) and bromo-acetic add tert.-butyl ester (3.77ml) are dissolved in dichloromethane (15ml) and to the stirred solution is added a solution of tetrabutylammonium hydrogen sulfate (2.05g) in aqueous sodium hydroxide (50% w/v, 25ml). The -mixture is stirred at 20°C for 4 hours and water (150ml) is added. The mixture is extracted with ethyl acetate (200 then 4x100ml), the combined extracts are dried (MgSθ4) and the solvent evaporated to give a pale orange oil which is purified by flash chromatography on a column of silicagel using etheπhexane (19:1, followed by 10:1 , by vol.) as eluant to give (2(S)-dibenzylamiπo-3-phenyl-propoxy)-acetic acid tert.-butyl ester as a colourless oil which is further purified by short path distillation (3mm Hg, 95°C). [M+H]⁺ = 446.2.

(ii) (2(S)-Dibeπzylamino-3-phenyl-propoxy)-acetic acid tert.-butyl ester (7.49g) is dissolved in dry THF (80ml) and lithium aluminium hydride in THF (1M, 67.2ml) is added to the stirred solution under an atmosphere of nitrogen keeping the temperature of the mixture below 5°C. The mixture is allowed to warm to room temperature, excess of reagent is destroyed

(water) and further water (200ml) is added The mixture is extracted with ethyl acetate (350 + 100ml) and the combined extracts are washed with bπne (200ml), dπed (MgSO₄) and the solvent evaporated to give 2-(2(S)- dιbenzylamιno-3-phenyl-propoxy)-ethanol as a colourless oil [M+H]⁺ =

376.2.

(in) 2-(2(S)-Dιbenzylamιno-3-phenyl-propoxy)-ethanol (6 22g) is dissolved in a mixture of methanol (75ml) and acetic acid (4ml) and the solution is hydrogenated (1 bar, 20°C, 17 hours) in the presence of 10% palladium on charcoal (1 18g) After removal of catalyst by filtration and of the solvent by rotary evaporation, 2-(2(S)-amιno-3-phenyl-propoxy)- ethanol is obtained as a light orange oil [M+H]⁺ = 196 0

d) 4-Chloro-pyπdιne-3-sulfonιc acid [2-(4-ethyl-pιpeπdιn-1-yl)-1(S)-(4-nιtro- benzyl)-2-oxo-ethyl]-amιde (1g) is added to a stirred solution of 2-(2(S)- amιno-3-phenyl-propoxy)-ethanol (934mg) and Huenig Base (3 62ml) in ethanol (5ml) and the reaction mixture is heated in a sealed vial at 100°C for 24 hours Puπfication of crude recovered mateπai by flash chromatography on a column of silicagel using dichloromethane methanol (19 1, by vol ) as eluant provides 4-[1 (S)-(2-hydroxy-ethoxymethyl)-2-phenyl-ethylamιno]- pyπdιne-3-sulfonιc acid [2-(4-ethyl-pιρeπdιn-1-yl)-1 (S)-(4-nιtro-benzyl)-2-oxo- ethylj-amide as a pale yellow foam [M+H]⁺ = 640 6

e) 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl-ethylamιno]-pyπdιne-3- sulfonic acid f2-(4-ethyl-pιpeπdιn-1-yl)-1 (S)-(4-nιtro-benzyl)-2-oxo-ethyl]- amide (335mg) is dissolved in methanol (30ml) and the solution is hydrogenated (1 bar, 20°C, 17 hours) in the presence of 10% palladium on charcoal (80mg) After removal of catalyst by filtration and of the solvent by rotary evaporation, the crude product is puπfied by flash chromatography on a column of silicagel using dichloromethane methanol (19 1 , by vol ) as eluant to give 4-[1(S)-(2-hydroxy-ethoxymethyl)-2-phenyl-ethylamino]- pyridine-3-sulfonic add [1(S)-(4-amino-benzyl)-2-(4-ethyl-piperidin-1-yl)-2- oxo-ethyl]-amide as a white foam. [M+H]⁺ = 610.4.

The following compounds are prepared similarly:

Example Structure [M+H]^* NMR

4a Methanesulfonic acid 2(S)-(3-{1(S)-benzothiazol-2- 704.3 1H, 13C ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethylsulfamoyl}-pyridiπ-4-ylamino)-3-phenyl-propyi ester

4b Toluene-4-sulfonic acid 2(S)-(3-{1(S)-benzothiazol- 780.6 1 H, 13C

2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin- 1 -yl]-2- oxo-ethylsulfamoyl}-pyridin-4-ylamino)-3-phenyf- propyl ester

4c [2(S (3-{1(S)-Benzyl-2-[4-(2-fluoro-ethyl)-piperidin- 683 1H

1-yl]-2-oxo-ethylsulfamoyi}-pyridin-4-ylamino)-3- phenyl-propoxyj-acetic acid tert.-butyl ester

4d 4-(1(S)-Dimethylaminomethyl-2^phenyl- 653.2 1H, 13C ethylamino)-pyridine-3-sulfonic acid (1(S) benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl}-amide

4e 4-(1(S)-Mθφholin-4-ylmethyl-2-phenyl-ethylamino)- 668.3 1H, 13C pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin-1 -yl]-1 (S)-(4-methoxy-benzyl)-2-oxo- ethyl]-amide f 4-(1 (S)-Benzyl-2-pyrrolidin-1-yl-ethylamino)- 652.3 1H, 130 pyridine-3-sulfonic add [2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-1(S)-(4-methoxy-benzyl)-2-oxo- ethyl]-amide

g 4-(1(S)-Mθφholin-4-ytmethyl-2-phenyl-ethylamino)- 684.3; 1H, 130 pyridine-3-sulfonic add [2-[4-(2-chloro-ethyl)- 686.2 piperidin-1-yl]-1(S)-(4-methoxy-benzyl)-2-oxo- ethyl]-amide

h 4-(1 (S)-Mθφholin-4-ytmethyl-2-phenyl-ethylamino)- 650.3 1 H pyridine-3-sulfonic acid [2-(4-ethyl-piperidin-1-yl)- 1(S)-(4-methoxy-benzyl)-2-oxo-ethylj-amide

i 4-(1(S)-Mθφholin-4-ylmethyl-2-phenyl-ethylamino)- 656.1 1H pyridine-3-sulfonic acid {1 (S)-(4-fluoro-benzyl)-2-[4- (2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide

j 4-(1(S)-Dimethylaminomethyl-2-phenyl- 612.2; 1 H ethylamino)-pyridine-3-sulfonic acid {1(S)-benzyl-2- 614.2 [4-(2-chloro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

k 4-(1 (S)-Dimethyiaminomethyl-2-phenyl- 626.3 1H ethylamino)-pyridine-3-sulfonic acid [2-[4-(2-fluoro- ethyl)-piperidin-1 -yl]-1 (S)-(4-methoxy-benzyl)-2- oxo-ethyl]-amide

41 4-(1 (S)-Dimethylaminomethyl-2-phenyl- 642.3; 1 H ethytamino)-pyridine-3-sulfonic acid [2-[4-(2-chloro- 644.2 ethyl)-pιpeπdιn-1 -yl]-1 (S)-(4-methoxy-beπzyl)-2- oxo-ethyl]-amιde

m 4-(1(S)-Dιmethylamιnomethyl-2-phenyl- 608 2 1H ethylamιno)-pyπdιne-3-sulfonιc acid [2-(4-ethyl- pipendin- 1 -yl)- 1 (S)-(4-methoxy-benzyl)-2-oxo- ethyl]-amιde

n 4-(1(S)-Dιmethylamιnomethyl-2-phenyl- 614 2 1H ethylamιno)-pyπdιne-3-sulfonιc acid {1(S)-(4-fiuoro- benzyl)-2-[4-(2-fluoro-ethyl)-pιpendιn-1-yl]-2-oxo- ethyl}-amιde

o 4-(2-Phenyl-1(S)-pyrrolιdιn-1-ylmethyl-ethylamιno)- 668 5, 1H, 130 pyπdιne-3-sulfonιc aαd [2-[4-(2-chioro-ethyl)- 670 5 pιpeπdιn-1-yl]-1(S)-(4-methoxy-benzyl)-2-oxo- ethyl]-amιde

p 4-(2-Phenyl-1(S)-pyπrolιdιn-1-ylmethyl-ethylamιno)- 640 6 1 H, 130 pyπdιne-3-sulfonιc acid {1(S)-(4-fluoro-benzyl)-2-{4- (2-fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-ethyl}-amιde

q 4-(1(S)-Beπzyl-2-pyrrolιdιn-1-yl-ethylamιno)- 622 2 1 H, 130 pyndιne-3-sulfonιc aαd {1(S)-benzyl-2-[4-(2-fluoro- ethyl)-pιpeπdιn- 1 -yl]-2-oxo-ethyl}-amιde

r 4-[1(S)-Benzyl-2-(4-hydroxy-pιpeπdιn-1-yl)- 668 2, 1H ethylamιno]-pyπdιne-3-sulfonιc acid {1(S)-benzyl-2- 670 1 [4-(2-chloro-ethyl)-pιpeπdιπ-1-yl]-2-oxo-ethyl}- amide s 4-[1(S)-Benzyl-2-(4-hydroxy-pιpeπdιn-1-yl)- 682.1 1H ethylamιno]-pyπdιne-3-sulfonιc aαd [2-[4-(2-fluoro- ethyl)-pιpeπdιn-1-yl]-1 (S)-(4-methoxy-benzyl)-2- oxo-ethyl]-amιde

t 4-[1(S)-Benzyl-2-(4-hydroxy-pιpeπdιn-1-yl)- 698.2, 1H ethylamιno]-pyπdιne-3-sulfonιc aαd [2-[4-(2-chloro- 700.2 ethyl)-pιpeπdιn-1-yl]-1(S)-(4-methoxy-benzyl)-2- oxo-ethyl]-amιde

u 4-[1(S)-Benzyl-2-(4-hydroxy-pιpeπdιn-1-yl)- 664 3 1 H ethylamιno]-pyπdine-3-sulfonιc acid [2-(4-ethyl- pιpeπdin-1-yl)-1(S)-(4-methoxy-benzyl)-2-oxo- ethyl]-amide

v 4-[1(S)-Benzyl-2-(4-hydroxy-pιpeπdιn-1-yl)- 670 1 1H ethylamιno]-pyπdιne-3-sulfonιc acid {1 (S)-(4-fluoro- benzyl)-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo- ethyl}-amιde

w 4-{1(S)-Benzyl-2-[4-(2-moφholιn-4-yl-2-oxo-ethyl)- 780 0, 1 H, 13C pιperazιn-1-yl]-ethylamιno}-pyπdιne-3-sulfonιc aαd 782.0 {1(S)-benzyl-2-[4-(2-chloro-ethyl)-pιpendιn-1-yl]-2- oxo-ethyl}-amιde

x 4-{1(S)-Benzyl-2-[4-(2-moφholιn-4-yl-2-oxo-ethyl)- 794 7 1H, 130 pιρerazιn-1-yl]-ethylamιno}-pyπdιne-3-sulfonic aαd [2-[4-(2-fluoro-ethyl)-pιpeπdιn-1-yl]-1 (S)-(4- methoxy-benzyl)-2-oxo-ethyl]-amιde

4y 4-{1(S)-Benzyl-2-[4-(2-mθφholιn-4-yl-2-oxo-ethyl)- 810 7, 1 H, 130 piperazin-1-yl]-ethylamino}-pyridine-3-sulfonic acid 811.8

[2-[4-(2-chloro-ethyl)-piperidin-1-yl]-1(S)-(4- methoxy-benzyl)-2-oxo-ethyl]-amide

z 4-{1(S)-Benzyl-2-[4-(2-moφholin-4-yl-2-oxo-ethyl)- 776.4 1H, 13C piperazin-1-yl]-ethylamino}-pyridine-3-sulfonic acid [2-(4-ethyl-piperidin- 1 -yl)- 1 (S)-(4-methoxy-benzyl)- 2-oxo-ethyϊ]-amide

aa 4- 1(S)-Benzyl-2-[4-(2-moφholin-4-yl-2-oxo-ethyl)- 782.1 1H, 130 piperazin- 1 -yl]-ethylamino}-pyridϊne-3-sulf onic acid {1(S)-(4-fluoro-benzyl)-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl}-amide

ab 4-(1(S)-Benzyl-3-hydroxy-propylamino)-pyridine-3- 583 1H sulfonic add (1(S)-benzyl-2-[4-(2-fluoro-ethyl)- piperidin- -yl]-2-oxo-ethyl}-amide

ac 4-(1(S)-Fluoromethyl-2-phenyl-ethylamino)- 628.6 pyridine-3-sulfonic acid {1(S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethyl)-amide

ad 4-[1(S)-(2-Methoxy-ethoxymethyl)-2-phenyl- 627.23 1H ethylamino]-pyridine-3-sulfonic acid {1(S)-benzyl-2- [4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide

ae 4- 1(S)-Benzyl-2-[4-(2-hydroxy-ethyl)-piperazin-1- 711.36 1H, 130 yl]-ethylamino}-pyridine-3-sulfonic acid [2-[4-(2- fluoro-ethyl)-piperidin-1 -yl]-1 (S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amide af 4-{1(S)-Benzyl-2-[4-(2-hydroxy-ethyl)-piperazin-1- 727.36; 1H, 130 yl]-ethylamino}-pyridine-3-sulfonic add [2-[4-(2- 728.44 chloro-ethyl)-piperidin-1 -yl]-1 (S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amide

ag 4-{1(S)-Benzyl-2-[4-(2-hydroxy-ethyl)-piperazin-1- 697.4; 1H, 130 ylJ-ethylamino}-pyridine-3-sulfonic acid {1 (S)- 699.4 benzyl-2-[4-(2-chloro-ethyl)-piperidin-1-yl]-2-oxo- ethyl}-amide

ah 4-(1(S)-Benzyl-4-hydroxy-butylamino)-pyridine-3- 596.9 1 H sulfonic acid {1 (S)-benzyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl}-amide

ai 4-{1(S)-Benzyl-2-[4-(moφholine-4-carbonyl)- 765.4; piperidin-1-yl]-ethylamino}-pyridine-3-sulfonic acid 767.4 {1 (S)-benzyl-2-[4-(2-chloro-ethyl)-piperidin-1 -yl]-2- oxo-ethyl}-amide

aj 4-{1 (S)-Benzyl-2-[4-(moφholine-4-caΦonyl)- 747.6 piperidin-1-yl]-ethylamino}-pyridine-3-sulfonic acid [2-(4-ethyl-piperidin-1 -yl)-1 (S)-(4-hydroxy-benzyl)- 2-oxo-ethyl]-amide

ak 4(S)-(3-{1(S)-Benzyl-2-[4-(2-fluoro-ethyl)-piperidin- 611.2 1H

1-yl]-2-oxo-ethylsulfamoyl}-pyridin-4-ylamino)-5- phenyl-pentanoic acid

al 4(R)-(3-{1(S)-Benzyl-2-[4-(2-fluoro-ethyl)-piperidin- 611.2

1-yl]-2-oxo-ethylsulfamoyl}-pyridin-4-ylamino)-5- phenyl-pentanoic acid

am 4-(1(S)-Mθφholin-4-ylmethyl-2-phenyl-ethylamino)- 654.2 1H pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

an 4-(1(S)-Moφholin-4-ylmethyl-2-phenyl-ethylamino)- 636.1 1H pyridine-3-sulfonic add [2-(4-ethyl-piperidin-1-yl)- 1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]-amide

ao 4-(1(S)-Dimethylaminomethyl-2-phenyl- 594.5 1 H ethylamino)-pyridine-3-sulfonic acid [2-(4-ethyl- piperidin-1-yl)-1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

ap 4-{1(S)-Benzyl-2-(4-hydroxy-piperidin-1-yl)- 650.4 1H ethylamino]-pyridine-3-sulfonic acid [2-(4-ethyl- piperidin-1-yl)-1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

aq 4-{1 (S)-Benzyl-2-[4-(2-moφholin-4-yl-2-oxo-ethyl)- 762 1H, 13C piperazin-1-yl]-ethylamino}-pyridine-3-sulfonic acid [2-(4-ethyl-piperidin-1-yl)-1(S)-(4-hydroxy-benzyl)- 2-oxo-ethyl]-amide

ar 4-{1(S)-Benzyl-2-[4-(2-hydroxy-ethyl)-piperazin-1- 697.31 1 H, 130 yl]-ethylamino}-pyridine-3-sulfonic acid [2-[4-(2- fluoro-ethyt)-piperidin-1-yl]-1(S)-(4-hydroxy-benzyl)- 2-oxo-ethyl]-amide as 4-{1(S)-Benzyl-2-[4-(2-hydroxy-ethyl)-piperazin-1- 679.41 1 H, 13C yl]-ethylamino}-pyridine-3-sulfonic acid [2-(4-ethyl- piperidin-1 -yl)-1 (S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

at 4-(2-Phenyl-1(S)-pyrrolidin-1-ylmethyl-ethylamino)- 620.4 1H, 13C pyridine-3-sulfonic acid [2-(4-ethyl-piperidin-1-yl)- 1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]-amide

au 4-(1(S)-Benzyl-2-pyrrolidin-1-yl-ethylamino)- 638.3 1H, 13C pyridine-3-sulfonic acid [2-[4-(2-flϋoro-ethyl)- piperidin-1-yl]-1(S)-(4-hydroxy-benzyl)-2-oxo-ethyl]- amide

av [2(S)-(3-{1(S)-(4-Amino-benzyl)-2-(4-(2-fluoro- 642.1 1H ethyl)-piperidin-1-yl]-2-oxo-ethylsulfamoyl}-pyridin- 4-ylamino)-3-phenyl-propoxy]-acetic acid

aw 4-[2-(4-Methoxy-phenyl)-1(S)-moφholin-4-ylmethyl- 683.2 1 H, 130 ethylamino]-pyridine-3-sulfonic acid {1(S)-(4-amino- benzyl)-2-[4-(2-fluoro-ethyi)-piperidin-1-yl]-2-oxo- ethyl}-amide

ax 4-(1(S)-Mθφholin-4-ylmethyl-2-phenyl-ethylamino)- 669.1; 1H pyridine-3-sulfonic acid {1 (S)-(4-amino-benzyl)-2- 671.1 [4-(2-chloro-ethyl)-piperidin-1-yl]-2-oxo-ethyl>- amide

ay 4-(1(S)-Benzyl-3-hydroxy-propylamino)-pyridine-3- 580.1 1H sulfonic acid [1(S)-(4-amino-benzyl)-2-(4-ethyl- piperidin-1-yl)-2-oxo-ethyl]-amide az 4-[1(S)-(2-Methoxy-ethoxymethyl)-2-phenyl- 624.27 1H ethylamino]-pyridine-3-sulfonic acid [1(S)-(4-amino- benzyl)-2-(4-ethyl-piperidin- 1 -yl)-2-oxo-ethyl]-amide

ba 4-(1(S)-Benzyl-4-hydroxy-butylamino)-pyridine-3- 593.7 1H sulfonic add [1 (S)-(4-amino-benzyl)-2-(4-ethyl- piperidin-1-yl)-2-oxo-ethyl]-amide

bb 4-{1(S)-Benzyl-2-[4-(2-hydroxy-ethyl)-piperazin-1- 677.9 1 H, 13C yl]-ethylamino}-pyridine-3-sulfonic acid [1(S)-(4- amino-benzyl)-2-(4-ethyl-piperidin-1-yl)-2-oxo- ethyl]-amide

bc 4-(1(S)-Benzyl-2-{4-[2-(2-hydroxy-ethoxy)-ethyl]- 721.9 1 H, 130 piperazin-1-yl}-ethylamino)-pyridine-3-sulfonic acid [1 (S)-(4-amino-benzyl)-2-(4-ethyi-piperidin- 1 -yl)-2- oxo-ethyl]-amide

bd 4-(1 (S)-Benzyl-2-pyrrolidin-1-yl-ethylamino)- 619.4 1 H, 130 pyridine-3-sulfonic acid [1(S)-(4-amino-benzyI)-2- (4-ethyl-piperidin-1-yl)-2-oxo-ethyl]-amide

be 4-(1(S)-Benzyl-2-pyrrolidin-1-yl-ethylamino)- 653.3; 1 H, 130 pyridine-3-sulfonic acid {1(S)-(4-amino-benzyl)-2- 655.3 [4-(2-chloro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}- amide

bf (2(S)- 3-[1(S)-(4-Amino-benzyl)-2-(4-ethyl-piperidin- 624.2 1H

1-yl)-2-oxo-ethylsulfamoyl]-pyridin-4-ylamino}-3- phenyl-propoxy)-acetic acid bg 4-(1(R)-Benzyl-4-hydroxy-butylamino)-pyridine-3- 593.8 1 H sulfonic add [1(S)-(4-amino-benzyl)-2-(4-ethyl- piperidin- 1 -yl)-2-oxo-ethyl]-amide

bh 4-(1(S)-Mθφholin-4-ylmethyl-2-phenyl-ethylamino)- 652.6 1H pyridine-3-sulfonic acid {1 (S)-benzyl-2-[4-(2-fluoro- ethyl)-piperidin- 1 -y l]-2-oxo-ethy l}-methyl-amide

bi 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 626.8 1 H ethylamino]-pyridine-3-sulfonic add {1 (S)-benzyl-2- [4-(2-f luoro-ethyl)-piperidin- 1 -y l]-2-oxo-ethy I}- methyl-amide

bj 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 642.33 1 H, 13C ethylamino]-pyridine-3-sulfonic acid [2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-1(S)-(4-methylamino-benzyl)- 2- oxo-ethyl]-amide

bk 4-(1(S)-Methoxymethyl-2-phenyl-ethytamino)- 611.7 1 H, 130 pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin- 1 -yl]- 1 (S)-(4-methylamino-benzyl)-2-oxo- ethyl]-amide

bl 4-(1(S)-Dimethylaminomethyl-2-phenyl- 625.5 1 H, 130 ethylamino)-pyridine-3-sulfonic acid [2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-1(S)-(4-methylamino-benzyl)- 2-oxo-ethyl]-amide

4bm 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 623.9 1 H, 130 ethylamino]-pyridine-3-sulfonic add [2-(4-ethyl- piperidin-1-yl)-1(S)-(4-methylamino-benzyl)-2-oxo- ethyl]-amide

bn 4-{1(S)-Benzyl-2-[4-(2-hydroxy-ethyl)-piperazin-1- 691.9 1H, 13C yl]-ethytamino}-pyridine-3-sulfonic acid [2-(4-ethyl- piperidin-1-yl)-1(S)-(4-methylamino-benzyl)-2-oxo- ethyt]-amide

bo 4-(1(S)-Benzyl-2-{4-[2-(2-hydroxy-ethoxy)-ethyl]- 735.9 130 piperazin-1-yl}-ethylamino)-pyridiήe-3-sulfonic acid [2-(4-ethyl-piperidin-1-yl)-1(S)-(4-methylamino- benzyl)-2-oxo-ethyl]-amide

bρ 4-(1(S)-Benzyl-2-pyrrolidin-1-yl-ethylamino)- 651.3 1 H, 130 pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-1(S)-(4-methylamino-benzyl)-2-oxo- ethyl]-amide

bq 4-(1(S)-Diethytaminomethyl-2-phenyl-ethylamino)- 653 1 H, 130 pyridine-3-suifonic acid [2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-1(S)-(4-methylamino-benzyl)-2-oxo- ethyl]-amide

br [2(S)-(3- 1(S)-Benzyl-2-[4-(2-fluoro-ethyl)-piperidin- 627.5 1H

1-yl]-2-oxo-ethytsulfamoyl}-pyridin-4-ylamino)-3- phenyl-propoxy]-acetic acid

bs 1-[2(S)-(3-{1(S)-Benzyl-2-[4-(2-chloro-ethyl)- 695.7; 1 H, 130 piperidin-1-yl]-2-oxo-ethylsulfamoyl}-pyridin-4- 697.7 ylamino)-3-phenyl-propyl]-piperidine-4-caΦoxylic add

bt 1-(2(S)-{3-[2-[4-(2-Chloro-ethyl)-piperidin-1-yl]-1(S)- 725.6; 1H, 13C

(4-methoxy-benzyl)-2-oxo-ethylsulf amoyl]-pyridin- 727.5 4-ylamino}-3-phenyl-propyl)-piperidine-4-caΦoxylic add

bu 1-[2(S)-(3-(1 (S)-(4-Amino-benzyl)-2-[4-(2-chloro- 711.0: 1 H, 130 ethyl)-piperidin-1-yl)-2-oxo-ethylsulfamoyl}-pyridin- 713.2 4-ylamino)-3-phenyl-propyl]-piperidine-4-caΦoxylic acid

bv 1-(2(SH3-[1(S)-(4-Amino-benzyl)-2-(4-ethyl- 675.2 1 H, 130 piperidin-1-yl)-2-oxo-ethylsulfamoyl] -pyridin-4- ylamino}-3-phenyl-propyl)-piperidine-4-caΦoxylic acid

bw 2-[2(S)-(3-{1 (S)-Benzyl-2-[4-(2-fluoro-ethyl)- 670.4 1 H piperidin-1-yl]-2-oxo-ethylsulfamoyl}-pyridin-4- ylamino)-3-phenyl-propoxy]-N-(2-hydroxy-ethyl)- acetamide

bx 4-[1(S)-(2-Moφholin-4-yl-2-oxo-ethoxymethyl)-2- 696.3 1H phenyl-ethylamino]-pyridine-3-sulfonic acid {1 (S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethyl}-amide

by 2-[2(S)-(3-{1(S)-Benzyl-2-[4-(2-fluoro-ethyl)- 654.4 1 H piperidin- 1 -yl]-2-oxo-ethylsulf amoyl}-pyridin-4- ylamino)-3-phenyl-propoxy]-N,N-dimethyl- acetamide bz 4-[1(S)-(2-Moφholin-4-yl-2-oxo-ethoxymethyl)-2- 711.5 1H phenyl-ethylamino]-pyridine-3-sulfonic acid {1 (S)- (4-amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

ca 2-[2(S)-(3-{1(S)-(4-Amino-benzyl)-2-[4-(2-fluoro- 669.3 1 H ethyl)-piperidiπ- 1 -yl]-2-oxo-ethylsulf amoyl}-pyridin- 4-ylamino)-3-pheπyl-propoxy]-N,N-dimethyl- acetamide

4cb [2(S)-(3-{1(SH4-(2-Fluoro-ethyl)-piperidine-1- 627.3 1 H caΦonyl]-2-phenyl-ethylsulfamoyl}-pyridin-4- ylamino)-3-phenyl-propoxy]-acetic add

Examples 4a to 4al omit the final hydrogenation step 4(e) of Example 4

Examples 4av and 4bf have a final saponification step

Example 4bd is a 77:23 mixture of diastereomers (by hplc analysis)

Example 4bg requires isolation by silicagel column chromatography from a mixture of diastereomers

Examples 4bh and 4bi - the assembly of both the N-methyl-amino acid and the complex side chain are conducted before final assembly (See the analogous Example 7(e))

Examples 4bh to 4bq - the assembly of both the aminomethyl-substituted amino acid and the complex side chain are conducted before final assembly. Hydrogenolytic deprotection is the final step (See the analogous

Example 7(e))

Examples 4br to 4bt require a final saponification step

Examples 4bu and 4bv require saponification to precede the final hydrogenation step Examples 4bw to 4by - modification of the side chain of the amino pyridine substituent is effected by 1 ,1-caΦonyl di-imadazole-assisted amide coupling as the last synthetic step

Examples 4bz and 4ca are as Examples 4bw to 4by with the addition of a final catalytic hydrogenation step

Example 4cb requires acidolytic deprotection as the final step

EXAMPLE 5

Analogously as described for Example 4(a-b) but using 4-(2-fluoro-ethyl)- piperidine in place of 4-ethyl-piperidine is prepared 4-chloro-pyridine-3- sulfonic add {2-(4-[2-fluoro-ethyl]-piperidin-1 -yl)-1 (S)-(4-nitro-benzyl)-2-oxo- ethyl}-amide. This is treated with 2(S)-amino-3-phenyi-propan-1-ol analogously as described for Example l (g) and the product, 4-[1(S)- hydroxymethyl-2-phenyl-ethylamino]-pyridine-3-sulfonic acid {2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-1(S)-(4-nitro-benzyl)-2-oxo-ethyl}-amide is obtained as a pale yellow solid after purification by flash chromatography on a column of silicagel using dichloromethane: methanol (25:1 , by vol.). This is reduced as described for Example 4(e) to give, after purification by flash chromatography on a column of silicagel using dichloromethane:methanol (25:1, by vol.) as eluant, 4-(1(S)-hydroxymethyl-2-phenyl-ethylamino)- pyridine-3-sulfonic acid {1 (S)-(4-amino-benzyl)-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethyl]-amide. [M+H]⁺ = 584.4.

The following compounds are prepared similariy:

Example Structure [M+H]⁺ NMR

5a 4-(2-Cyclohexyl-1(S)-hydroxymeth l- 590.3 1 H, 13C ethylamino)-pyridine-3-sulfonic acid {1 (S)-(4- amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethy!}-amide

5b 4-[1(S)-Hydroxymethyl-2-(4-methoxy-phenyl)- 614.4 1 H, 13C ethylamino]-pyridine-3-sulfonic acid {1 (S)-(4- amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

5c 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 628.3 1 H ethylamino]-pyridine-3-sulfonic acid {1(S)-(4- amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

5d 4-(1(R)-Methyl-2-phenyl-ethylamino)-pyridine-3- 568.3 1H, 13C sulfonic add {1(S)-(4-amino-benzyl)-2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide

5e 4-[2-(4-Methoxy-phenyl)-1(R)-methyl- 598.3 1H, 130 ethylamino]-pyridine-3-sulfonic acid {2-(4-amino- phenyl)-1(S)-[4-(2-fluoro-ethyl)-piperidine-1- caΦonyl]-ethyl}-amide

5f 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 566.3 1 H, 130 pyridine-3-sulfonic acid [2-(4-amino-phenyl)- 1(S)-(4-ethyl-pιpeπdine-1-caΦonyl)-ethyl]-amιde

g 4-(2-Cydohexyl-1(S)-hydroxymethyl- 572.2 ethylamιno)-pyπdine-3-sulfonic acid [1 (S)-(4- amιno-benzyl)-2-(4-ethyl-pιpeπdιn-1-yl)-2-oxo- ethyl]-amιde

h 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamιno)- 600 1 , 1 H, 13C pyπdιne-3-sulfonιc aαd {1 (S)-(4-amιno-benzyl)- 601 7 2-[4-(2-chloro-ethyl)-pιpeπdιn-1-yl]-2-oxo-ethyl}- amide

i 4-[1(S)-Hydroxymethyl-2-(4-methoxy-phenyl)- 630.0, 1 H, 13C ethylamιno]-pyπdιne-3-sulfonιc aαd {1 (S)-(4- 631 9 amιno-benzyl)-2-[4-(2-chloro-ethyl)-pιpeπdιn-1- yl]-2-oxo-ethyl}-amιde

j 4-[1(S)-Hydroxymethyl-2-(4-methoxy-phenyl)- 596 7 1H, 13C ethylamιno]-pyπdιne-3-sulfonιc aαd [1(S)-(4- amιno-benzyl)-2-(4-ethyl-pιpeπdιn- 1 -yl)-2-oxo- ethyl]-amιde

k 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamιno)- 600 2 1 H, 130 pyndιne-3-sulfonιc aαd {1 (S)-(3-amιno-4- hydroxy-benzyl)-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1- yl]-2-oxo-ethyl}-amide

1 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 610.3 1 H, 130 ethylamιno]-pyndιne-3-sulfonιc acid [1 (R)-(4- amιno-benzyl)-2-(4-ethyl-pιpendιn- 1 -yl)-2-oxo- ethyl]-amιde m 4-[2-(3,4-Dimethoxy-phenyl)-1(S)- 644.2 1 H hydroxymethyl-ethylamino]-pyridine-3-sulfonic add {1 (S)-(4-amino-benzyl)-2-[4-(2-fluoro-ethyl)- piperidin-1 -yl]-2-oxo-ethyl)-amide

n 4-[2-(3,4-Dimethoxy-phenyl)-1(S)- 660.5; 1 H hydroxymethyl-ethylamino]-pyridine-3-sulfonic 662.5 add {1 (S)-(4-amino-benzyl)-2-[4-(2-chloro- ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide

o 4-[2-(3,4-Dimethoxy-phenyl)-1(S)- 626.2 1 H hydroxymethyl-ethylamino]-pyridine-3-sulfonic add [1 (S)-(4-amino-benzyl)-2-(4-ethyl-piperidin- 1 -yl)-2-oxo-ethyl]-amide

p 4-[1(S)-(2-Hydroxy-ethoxymethyl)-2-phenyl- 644.16 1 H, 13C ethylamino]-pyridine-3-sulfonic acid £1(S)-(4- amino-benzyl)-2-[4-(2-chloro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

q 4-(2-fra/7S-Phenyl-cyclopropylamino)-pyridine-3- 565.6 1 H, 130 sulfonic acid {1(S)-(4-amino-benzyl)-2-[4-(2- fluoro-ethyl)-piperidin-1-yϊ]-2-oxo-ethyl}-amide

r 4-(1(S)-Methoxymethyl-2-phenyl-ethylamino)- 613.8 1H, 13C pyridine-3-sulfonic add {1(S)-(4-amino-benzyl)- 2-[4-(2-chloro-ethyl)-piperidin- 1 -yl]-2-oxo-ethyl}- amide

s 4-(1(S)-Hydroxymethyl-3-methylsulfanyl- 567.7 1H, 130 propylamιno)-pyπdιne-3-sulfonιc acid {1 (S)-(4- amιno-benzyl)-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1- y l]-2-oxo-eth y l}-am ide

5t 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamιno)- 582.2 1H pyridιne-3-sulfonιc acid {1(S)-(4-amιno-benzyl)- 2-[4-(2-hydroxy-ethyl)-pιpeπdιn- 1 -yl]-2-oxo- ethylj-amide

Example 5t is obtained by saponification of the 2-acetyloxyethyl precursor

The following are prepared by treatment of Example 5k with tnethyl orthofonmate and tnethyl orthoacetate respectively under standard conditions

5u 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamιno)- 610.3 1H pyπdιne-3-sulfonιc acid {1 (S)-benzooxazol-5- ylmethyl-2-[4-(2-f luoro-ethyl)-pιpeπdιn- 1 -y l]-2-oxo- ethyf}-amιde

5v 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamιno)- 624 4 1 H, 13C pyπdιne-3-sulfonιc acid [2-[4-(2-fluoro-ethyl)- pιpeπdιn-1-yl]-1(S)-(2-methyl-benzooxazol-5- yimethyl)-2-oxo-ethyl]-amιde

EXAMPLE 6

a) 4-[1(S)-Hydroxymethyl-2-phenyl-ethylamιno]-pyndιne-3-sulfonιc acid {2-[4-(2- fluoro-ethyl)-pιpeπdιn-1-yl]-1(S)-(4-nιtro-benzyl)-2-oxo-ethyl}-amιde (2.6g) is dissolved in dichloromethane (20ml), tπethylamine (1 21ml) is added and the stirred mixture is cooled to 0°C under an atmosphere of nitrogen Methanesulfonyl chlonde (0 54ml) is added and the reaction is stirred at ice temperature for 2 hours. The mixture is extracted with ethyl acetate (50ml), the extract is washed with aqueous hydrochloric acid (2M, 20ml) and saturated aqueous sodium bicarbonate (20ml), dried (MgSU4) and solvent evaporated to give 4-(1 (S)-methanesulfonylmethyl-2-phenyl-ethylamino)-pyridine-3-sulfonic add

[2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-1(S)-(4-nitro-benzyl)-2-oxo-ethyl]-amide as a crisp, yellow foam. [M+H]⁺ = 647.2.

b) 4-(1(S)-Methanesulfonylmethyl-2-phenyl-ethylamino)-pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)-piperidin-1 -yl]-1 (S)-(4-nitro-benzyl)-2-oxo-ethyl]- amide (450mg) is dissolved in ethanol (20ml), moφholine (4ml) is added and the mixture is heated at reflux for 4 hours. After removal of solvent by rotary evaporation, the residue is purified by flash chromatography on a column of silicagel using dichloromethane: methanol (19:1, by vol.) as eluant to give 4- (1(S)-moφhoiin-4-ylmethyl-2-phenyl-ethylamino)-pyridine-3-sulfonic acid {1(S)-(4-nitro-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. [M+H]⁺ = 683.3.

c) 4-(1 (S)-Mθφholin-4-ylmethyl-2-phenyl-ethylamino)-pyridine-3-sulfonic acid {1(S)-(4-nitro-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide is catalytically reduced as described for Example 4(e) to give 4-(1(S)-moφholin-4- ylmethyl-2-phenyl-ethylamino)-pyridine-3-sulfonic acid {1 (S)-(4-amino-benzyl)-2-[4- (2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. [M+H]⁺ = 653.1.

The following compounds are prepared similarly:

Example Structure [M+H]⁺ NMR

6a 4-(1(S)-Azidomethyl-2-phenyl-ethylamino)- 651.3 1 H, 13C pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide b 4-(1(S)-Methylaminomethyl-2-phenyl- 582.2 1H ethylamino)-pyridine-3-sulfonic acid {1 (S)- beπzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

c 4-(1(S)-Dimethylaminomethyl-2-phenyl- 596.2 1 H ethylamino)-pyridine-3-sulfonic acid {1 (S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

d 4-[1(S)-Benzyl-2-(4-hydroxy-piperidin-1-yl)- 652.4 1H ethylamino]-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-f luoro-ethyl)-piperidin- 1 -yl]-2- oxo-ethyl}-amide

e 4-(1(S)-Benzyl-2-pyrrolidin-1-yl-ethylamino)- 638.2; 1 H, 13C pyridine-3-suifonic acid {1 (S)-benzyl-2-[4-(2- 640.1 chloro-ethyl)-piperidin-1-yl]-2-oxo-ethyl)-amide

f 4-(2-Cydohexyl-1(S)-methylaminomethyl- 604.2; 1H, 130 ethylamino)-pyridine-3-sulfonic acid {1 (S)- 606.1 benzyl-2-[4-(2-chloro-ethy l)-piperidin- 1 -y l]-2- oxo-ethyf}-amide

g 4-{1(S)-Benzyl-2-[4-(moφhoiine-4-carbonyl)- 749.3 1 H, 13C piperidin-1-yl]-ethylamino}-pyridine-3-sulfonic add {1 (S)-benzyl-2-[4-(2-fluoro-ethyl)-piperidin- 1 -yl]-2-oxo-ethyl>-amide

h Acetic acid 2-{1-[2(S)-(3-{1(S)-benzyl-2-[4-(2- 722.4 1 H fluoro-ethyl)-piperidin- 1 -yl]-2-oxo- ethylsulfamoyl}-pyridin-4-ylamino)-3-phenyl- propyl]-piperidin-4-yl}-ethyl ester

i 4-(1(S)-Mθφholin-4-ylmethyl-2-phenyl- 638.2 1H, 13C ethylamino)-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

j 4-(1(S)-Diethylaminomethyl-2-phenyl- 624.3 ethylamino)-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

k 4-(2-Cyclohexyl-1(S)-methylaminomethyl- 634.3; 1H, 13C ethyiamino)-pyridine-3-sulfonic acid [2-[4-(2- 636.3 chloro-ethyl)-ρiperidin-1-yl]-1(S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amide

1 1-[2(S)-(3-{1(S)-Benzyl-2-[4-(2-fluoro-ethyl)- 735.5 1 H piperidin-1-yl]-2-oxo-ethylsulfamoyl}-pyridin-4- ylamino)-3-phenyl-propyl]-piperidine-4- caΦoxylic acid diethylamide

m 4-(1(S)-Diethylaminomethyl-2-phenyl- 640.4; 1 H, 13C ethylamino)-pyridine-3-sulfonic acid (1(S)- 642.4 benzyl-2-[4-(2-chloro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

n 4-[1(S)-Benzyl-2-(3-oxo-piρerazin-1-yl)- 651.3 1H, 130 ethylamino]-pyridine-3-sulfonic acid {1(S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin- -yl]-2- oxo-ethyl}-amide

o 4-(1(S)-Moφholin-4-ylmethyl-2-phenyl- 654.2 1 H, 130 ethylamino)-pyridine-3-sulfonic acid {1 (S)- benzyl-2-[4-(2-chloro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

p 4-[2-(4-Acetyl-piperazin-1-yl)-1(S)-benzyl- 679.1 1H, 130 ethylamino]-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-fluoro- ethyl)-piperidin- 1 -yl]-2-oxo-ethyl}-amide

q 4-(1(S)-fJBis-(2-methoxy-ethyl)-amino]-methyl}- No 1H, 130

2-phenyl-ethylamino)-pyridine-3-sulfonic acid parent

{1 (S)-benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1 - ion yl]-2-oxo-ethyl}-amide

r 4-(2-Phenyl-1(SH(pyridin-2-ylmethyl)-amino]- 659.6 1H, 130 methyl}-ethylamino)-pyridine-3-sulfonic acid {1 (S)-benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1 - yl]-2-oxo-ethyl}-amide

s 4-(1(S)-Butylaminomethyl-2-phenyl- 670.5; tH, 130 ethylamino)-pyridine-3-sulfonic acid [2-[4-(2- 672.5 chloro-ethyl)-piperidin- 1 -yl]- 1 (S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amide

t 4-(1(S)-Butylaminomethyl-2-ρhenyl- 654.5 1 H, 130 ethylamino)-pyridine-3-sulfonic acid [2-[4-(2- fluoro-ethyl)-piperidin-1 -yl]-1 (S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amιde

u 4-{1(S)-Benzyl-2-[4-(2-hydroxy-ethyl)- 681 3 1H pιperazιn-1-yl]-ethylamιno}-pyπdιne-3-sulfonιc aαd {1 (S)-benzyl-2-[4-(2-fluoro-ethyl)-pιpeπdιn- 1 -yl]-2-oxo-ethyl}-amιde

v 4-(1(S)-Dιethylamιnomethyl-2-phenyl- 654 2 1H, 13C ethylamιno)-pyπdιne-3-sulfonιc acid [2-[4-(2- fluoro-ethyl)-pιpeπdιn-1-yl]-1(S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amιde

w 4-(1(S)-Benzyl-2-(4-[2-(2-hydroxy-ethoxy)- 725.4 1H ethyl]-pιperazιn- 1 -yl}-ethylamιno)-pyπdιne-3- sulfonic acid {1(S)-benzyl-2-[4-(2-fluoro-ethyl)- pιpendιn-1-yl]-2-oxo-ethyl}-amιde

x 4-(1(S)-Dιethylamιnomethyl-2-phenyl- 670.2, 1 H, 13C ethylamιno)-pyπdιne-3-sulfonιc acid [2-[4-(2- 672.2 chloro-ethyl)-pιpeπdιn-1-yl]-1(S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amιde

y 4-(1(S)-Chloromethyl-2-phenyl-ethylamιno)- 587.1 , 1H pyπdine-3-sulfonιc acid {1 (S)-benzyl-2-[4-(2- 589.6 fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-ethyr}-amιde

z 4-(2-Phenyl-1 (SH(pyπdin-4-ylmethyl)-amιno]- 659 3 1 H, 13C methyl}-ethylamιno)-pyπdιne-3-sulfonιc aαd {1 (S)-benzyl-2-[4-(2-f luoro-ethyl)-pιpeπdιn- 1 - yl]-2-oxo-ethyl}-amιde aa 1-[2(S)-(3-{1 (S)-Benzyl-2-[4-(2-fluoro-ethyl)- 737 3 1 H, 130 pipeπdin- 1-yl]-2-oxo-ethylsulfamoyϊ}-pyndιn-4- ylamιno)-3-phenyl-propyl]-pιpendιne-4- caΦoxylic acid (2-methoxy-ethyl)-amιde

ab 1-[2(S)-(3- 1(S)-Benzyl-2-[4-(2-fluoro-ethyl)- 721.2 1H, 130 pιpeπdιn-1-yl]-2-oxo-ethylsulfamoyl}-pyπdιn-4- ylamιno)-3-phenyl-propyl]-pιpeπdιne-4- caΦoxylic acid propylamide

ac 4-(1(S)-{IBιs-(2-methoxy-ethyl)-amιno]-methyl}- 714 2 1H

2-phenyl-ethylamιno)-pyπdιne-3-sulfonιc aαd [2-[4-(2-fluoro-ethyl)-pιpeπdιn-1 -yl]-1 (S)-(4- methoxy-benzyl)-2-oxo-ethyl]-amιde

ad 4-[2-(4-Acetyl-pιperazιn-1-yl)-1(S)-benzyl- 696 1 , 1H, 130 ethylamιno]-pyπdιne-3-sulfonιc acid (1(S)- 698 1 benzyl-2-[4-(2-chloro-ethyl)-pιpeπdιn-1-yl]-2- oxo-ethyl}-amιde

ae 4-[2-(4-Acetyl-pιperazιn-1-yl)-1(S)-benzyl- 709.2 1 H, 130 ethylamιno]-pyπdιne-3-sulfonιc aαd [2-[4-(2- fluoro-ethyl)-pιpeπdιn-1-yl]-1(S)-(4-methoxy- benzyl)-2-oxo-ethyl]-amιde

af 4-[2-(4-Acetyl-pιperazιn-1-yl)-1(S)-benzyl- 697 31 1H, 130 ethylamιno]-pyndine-3-sulfonιc acid {1 (S)-(4- fluoro-benzyl)-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1- yl]-2-oxo-ethyl}-amιde

ag 4-(1(S)-{[Bιs-(2-methoxy-ethyl)-amιno]-methyl}- 700 2, 2-phenyl-ethylamino)-pyridine-3-sulfonic add 702.2

{1(S)-benzyl-2-[4-(2-chloro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

ah 4-[1 (S)-Benzyl-2-(3-oxo-piperazin-1-yl)- 681.4; ethylamino]-pyridine-3-sulfonic acid (1(S)- 683.4 benzyl-2-[4-(2-chloro-ethyl)-piperidin-1-yl]-2- [M+CH_sf oxo-ethyl}-amide

ai 4-{1 (S)-(Methanesulfonylamino-methyl)-2- No 1 H, 13C phenyl-ethylamino]-pyridine-3-sulfonic add parent {1(S)-benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1- ion yl]-2-oxo-ethyl}-amide

aj 4-[1 (S)-(2-Hydroxy-ethylsulfanylmethyl)-2- 628.8 1 H phenyl-ethylamino]-pyridine-3-sulfonic acid {1(S)-benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

ak 4-[1 (S)-Benzyl-2-(1 ,1-dioxo-thiomoφholin-4- 701.2 1 H yl)-ethylamino]-pyridine-3-sulfonic add {1 (S)- (4-amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin- 1 -yl]-2-oxo-ethyl}-amide

al {[2(S)-(3-{1 (S)-(4-Amino-benzyl)-2-[4-(2-fluoro- 711.1 1 H, 130 ethyl)-piperidin-1-yl]-2-oxo-ethylsulfamoyl}- pyridin-4-ylamino)-3-phenyl-propyl]-methyl- amino}-acetic acid tert.-butyl ester

am [(2(S)-{3-[2-[4-(2-Fluoro-ethyl)-piperidin-1-yl]- No 1H, 130

1 (S)-(4-hydroxyamino-benzyl)-2-oxo- parent ethylsulfamoyl]-pyπdιn-4-ylamιno}-3-phenyl- ion propyl)-methyl-amιno]-acetιc acid tert.-butyl ester

an {[2(S)-(3-{1 (S)-(4-Amιno-benzyl)-2-[4-(2-fluoro- 655.1 1 H, 13C ethyl)-pιpeπdιn- 1 -yl]-2-oxo-ethylsu!f amoyl)- pyπdιn-4-ylamιno)-3-phenyl-propyl]-methyl- amιno}-acetιc acid

ao 1-(2(S)-{3-[2-[4-(2-Fluoro-ethyi)-pιpendιn-1-yl]- 709 8

1 (S)-(4-methoxy-benzyl)-2-oxo-ethylsulfamoyl]- pyπdιn-4-ylamιno}-3-phenyl-propyl)-pιpeπdιne- 4-caΦoxylιc acid

ap 1-[2(S)-(3-{1(S)-(4-Fluoro-benzyl)-2-[4-(2- 697 8 fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo- ethylsulfamoyl}-pyndιn-4-ylamιno)-3-phenyl- propyl]-pιpeπdιne-4-carboxylιc aαd

aq 4-(1(S)-Dιmethylamιnomethyl-2-phenyl- 612 4 1 H, 13C ethylamιno)-pyrιdιne-3-sulfonιc acid [2-[4-(2- fluoro-ethyl)-pιperιdιn-1-yl]-1(S)-(4-hydroxy- benzyl)-2-oxo-ethyl]-amιde

ar 4-(2-Cyclohexyl-1 (S)-methylamιnomethyl- 586.3 1H, 13C ethylamιno)-pyndιne-3-sulfonιc acid [2-(4-ethyl- pιpeπdιn-1-yl)-1 (S)-(4-hydroxy-benzyl)-2-oxo- ethyl]-amιde

as 4-(1(S)-Dιethylamιnomethyl-2-phenyl- 622.6 1 H, 130 ethylamιno)-pyπdιne-3-sulfonιc aαd [2-(4-ethyl- piperidin-1-yl)-1(S)-(4-hydroxy-benzyl)-2-oxo- ethyl]-amide

at 4-[2-(4-Acetyl-piperazin-1-yl)-1(S)-benzyl- 677.23 1H ethyiamino]-pyridine-3-sulfonic acid [2-(4-ethyl- piperidin-1-yl)-1(S)-(4-hydroxy-benzyl)-2-oxo- ethyl]-amide

au 4-(1 (S)-{[Bis-(2-methoxy-ethyl)-amino]-methyl}- 682.4 1 H, 13C

2-phenyl-ethylamino)-pyridine-3-sulfonic acid [2-(4-ethyl-piperidin-1-yl)-1(S)-(4-hydroxy- benzyl)-2-oxo-ethyl]-amide

av 4-(1 (S)-Methylaminomethyl-2-phenyl- 597.6 1H ethylamino)-pyridine-3-sulfonic acid {1(S)-(4- amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

aw 4-(1(S)-Dimethylaminomethyl-2-phenyl- 611.2 1H ethylamino)-pyridine-3-sulfonic acid {1(S)-(4- amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

ax 4-(2-Phenyl-1(S)-propylaminomethyl- 625.3 1H ethylamino)-pyridine-3-sulfonic acid {1(S)-(4- amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

ay 4-(1 (S)-Ethylaminomethyl-2-phenyl- 611.3 1H ethylamino)-pyridine-3-sulfonic acid {1(S)-(4- amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amιde

az 4-(2-Cyclohexyl-1(S)-methylamιnomethyl- 603.3 1 H, 130 ethylamιno)-pyπdιne-3-sulfonιc acid {1 (S)-(4- amιno-benzyl)-2-[4-(2-fluoro-ethyl)-piperidιn-1- yl]-2-oxo-ethyl}-amιde

ba 4-(1(S)-Butylamιnomethyl-2-phenyl- 639 4 1H ethylamιno)-pyπdιne-3-sulfonιc acid {1(S)-(4- amino-benzyi)-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1- yl]-2-oxo-ethyl}-amιde

bb 4-(1(S)-Benzyl-2-ρyrrolιdιn-1-yl-ethylamιno)- 637.4 1H pyridine-3-sulfonιc acid {1(S)-(4-amιno-benzyl)- 2-[4-(2-fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-ethyl}- amide

bc 4-(1(S)-Dιethylamιnomethyl-2-phenyl- 639 4 1H ethylamιno)-pyrιdιne-3-sulfonιc acid {1(S)-(4- amιno-benzyl)-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1- yl]-2-oxo-ethyl}-amιde

bd 4-(2-Cyclohexyl-1 (S)-dimethylamιnomethyl- 617.3 1H ethylamino)-pyπdine-3-sulfonιc acid {1 (S)-(4- amιno-benzyl)-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1- yl]-2-oxo-ethyl}-amιde

be 4-(2-Cyclohexyl-1(S)-ethylamιnomethyl- 617 4 1 H ethyiamιno)-pyπdιne-3-sulfonιc aαd {1(S)-(4- amιno-benzyl)-2-[4-(2-fluoro-ethyl)-pipeπdιn-1- yl]-2-oxo-ethyl}-amιde bf 4-{1(S)-[(2-Hydroxy-ethylamιno)-methyl]-2- 627.3 1H phenyl-ethylamιno}-pyπdιne-3-sulfonιc acιd {1(S)-(4-amιno-benzyl)-2-[4-(2-fluoro-ethyl)- pιpeπdιn-1 -yl]-2-oxo-ethyl>-amιde

bg 4-(2-Phenyl-1(S)-pιpeπdιn-1 -ylmethyl- 651.3 1 H ethylamιno)-pyπdιne-3-sulfonιc acid {1 (S)-(4- amιno-benzyl)-2-(4-(2-fluoro-ethyl)-pιpeπdιn-1- yl]-2-oxo-ethyl}-amιde

bh 4-(2-Phenyl-1(S)-thιomoφholιn-4-ylmethyl- 669 3 1H ethylamιno)-pyrιdιne-3-sulfonιc acid {1 (S)-(4- amιno-benzyl)-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1- yl]-2-oxo-ethyl}-amιde

bι 4-(1(S)-Chloromethyl-2-phenyl-ethylamιno)- 602.0, 1 H pyπdιne-3-sulfonιc acid {1(S)-(4-amιno-benzyl)- 604 0 2-[4-(2-fluoro-ethyl)-pιpeπdιn-1-yl]-2-oxo-ethy[}- amide

bj 4-[1(S)-Benzyl-2-(4-hydroxy-pιpeπdιn-1-yl)- 667.2 1H ethylamιnoj-ρyπdιne-3-sulfonιc acid {1 (S)-(4- amιno-benzyt)-2-[4-(2-fluoro-ethyl)-pιpeπdιn-1- yl]-2-oxo-ethyl}-amιde

bk 4- 1(S)-[(2-Methoxy-ethylamιno)-methyl]-2- 641.6 1 H phenyl-ethylamιno}-pyπdιne-3-sulfonιc acιd {1(S)-(4-amιno-benzyl)-2-[4-(2-fluoro-ethyl)- pιpeπdιn-1-yl]-2-oxo-ethyl}-amιde bl 4-(1(SH[Bιs-(2-methoxy-ethyl)-amιno]-methyl}- 699.6 1 H

2-phenyl-ethylamιno)-pyπdιne-3-sulfonιc aαd

{1(S)-(4-amιno-benzyl)-2-[4-(2-fluoro-ethyl)- pιpeπdιn-1-yl]-2-oxo-ethyl}-amιde

bm 1-[2(S)-(3-{1(S)-(4-Amιno-benzyl)-2-C4-(2- 723.2 1H fluoro-ethyl)-pιpeπdιn- 1 -yl]-2-oxo- ethylsulfamoyl]-pyπdιn-4-ylamιno)-3-phenyl- propyl]-pιpeπdιne-4-carboxylιc acid ethyl ester

bn 4-(1(S)-Mθφholιn-4-ylmethyl-2-phenyl- 635.3 1 H, 13C ethylamιno)-pyπdιne-3-sulfonιc acid [1(S)-(4- amιno-benzyl)-2-(4-ethyl-pιpeπdιn-1-yl)-2-oxo- ethyl]-amιde

bo 4-[2-(4-Acetyl-pιperazιn-1-yl)-1(S)-benzyl- 694.2 1 H ethylamιno]-pyπdιne-3-sulfonιc acid {1(S)-(4- amιno-benzyl)-2-[4-(2-fluoro-ethyl)-pιpeπdιn- 1 - yl]-2-oxo-ethyl}-amιde

bp 4-[2-(4-Acetyl-pιρerazιn-1-yl)-1(S)-benzyl- 676 4 1H ethylamιno]-pyndιne-3-sulfonιc acid [1 (S)-(4- amιno-benzyl)-2-(4-ethyl-pιpeπdιn-1-yl)-2-oxo- ethyl]-amιde

bq 4-(1(S)-{IBιs-(2-methoxy-ethyi)-amιno]-methyl>- 681 4

2-phenyl-ethylamιno)-pyπdιne-3-suifomc aαd [1(S)-(4-amιno-benzyl)-2-(4-ethyl-pιpeπdιn-1- yl)-2-oxo-ethyl]-amιde

br 4-[1(S)-Benzyl-2-(3-oxo-pιperazιn-1-yl)- 648 6 ethylamino]-pyridine-3-sulfonic acid [1(S)-(4- amino-benzyt)-2-(4-ethyl-piperidin-1-yl)-2-oxo- ethyl]-amide

bs 4-[1(S)-Benzyl-2-(3-oxo-piperazin-1-yl)- 666.6 ethylamino]-pyridine-3-sulfonic acid {1 (S)-(4- amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

bt 4-[2-(4-Acetyl-piperazin-1-yl)-1(S)-benzyl- 710.4 ethylamino]-pyridine-3-sulf onic add {1 (S)-(4- amino-benzyl)-2-[4-(2-chloro-ethyl)-piperidin-1- yl]-2-oxo-ethyl}-amide

bu 4-[1(S)-(2-Hydroxy-ethylsulfanylmethyl)-2- 643.8 1H phenyl-ethylamino]-pyridine-3-sulfonic add {1(S)-(4-amino-benzyl)-2-[4-(2-fluoro-ethyl)- piperidin- 1 -yl]-2-oxo-ethyl}-amide

bv 1-[2(S)-(3-{1(S)-(4-Amino-benzyl)-2-[4-(2- 695 1H fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethylsulfamoyl}-pyridin-4-ylamino)-3-phenyl- propyl]-piperidine-4-caΦoxylic acid

bw .N.-(2(S)-{3-[2-[4-(2-Fluoro-ethyl)-piperidin-1- 709.3 1 H, 130 y l]-2-oxo- 1 (S)-(4-propionylamino-benzyl)- ethylsulfamoyl]-pyridin-4-ylamino}-3-phenyl- propyl)-N-methyl-propionamide

bx 4-{1(S)-[(3-Ethyl-ureido)-methyl]-2-phenyl- 639.4 1H ethylamino}-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyf}-amide

by 4-(2-Phenyl-1(S)-piperazin-1-ylmethyl- 638.4 1H ethylamino)-pyridine-3-sulfonic acid (1(S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

bz 4-[1(S)-(3-Ethyl-1-methyl-ureidomethyl)-2- 668.4 1 H phenyl-ethylamino]-pyridine-3-sulfonic aαd {1(S)-(4-amino-benzyl)-2-[4-(2-flϋoro-ethyl)- piperidin- 1 -yl]-2-oxo-ethyl)-amide

ca 4-{1(S)-Benzyl-2-[4-(2-hydroxy-ethyl)-piperidin- 680.3 1 H

1-yl]-ethylamino}-pyridine-3-suifonic acid {1(S)- benzyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyi}-amide

cb 1-[2(S)-(3-{1 (S)-Benzyl-2-[4-(2-fluoro-ethyl)- 680.1 1 H, 130 piperidin-1-yl]-2-oxo-ethylsulfamoyl}-pyridin-4~ ([M+Na]^* ylamino)-3-phenyl-propyl]-piperidine-4- ) caΦoxylic acid

cc 4-(1(S)-Mercaptomethyl-2-phenyl-ethylamino)- 584.7 1H pyridine-3-sulfonic acid {1 (S)-benzyl-2-[4-(2- fluoro-ethyl)-piperidin- 1 -yl]-2-oxo-ethyl}-amide

cd 4-(1(S)-Aminomethyl-2-phenyl-ethylamino)- 568.4 1H pyridine-3-sulfonic acid {1(S)-benzyl-2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyi)-amide ce 4-(1 (S)-Aminomethyl-2-phenyl-ethylamino)- 625.2 1 H, 130 pyridine-3-sulfonic acid {1 (S)-benzothiazol-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-amide

cf 4-[1 (S)-(2-Hydroxy-ethylsulfanylmethyl)-2- 626 1 H phenyl-ethylamino]-pyridine-3-suifonic acid [1 (S)-(4-amino-benzyl)-2-(4-ethyl-piperidin- 1 - yl)-2-oxo-ethyl]-amide

cg N-(2(S)-{3-[2-[4-(2-Fluoro-ethyl)-^'piperidin-1-yl]- 669.2 1H, 13C

1(S)-(4-nitro-benzyl)-2-oxo-ethylsulfamoyl]- pyridin-4-ylamino}-3-phenyl-propyl)-N-methyl- acetamide

ch N-[2(S)-(3-{1(S)-(4-Amino-benzyl)-2-[4-(2- 639.4 1 H, 130 fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethylsulfamoyl}-pyridin-4-ylamino)-3-phenyl- propyl]-N-methyi-acetamide

ci 4-(2-Cyclohexyl-1(S)-methylaminomethyl- 606.3 1 H, 130 ethylamino)-pyridine-3-sulfonic acid [1(S)-[4- (2-fluoro-ethyl)-piperidine-1-caΦonyl]-2-(4- fluoro-phenyl)-ethyl]-amide

cj 4-(1(S)-Diethylaminomethyl-2-phenyl- 641.9 1H ethylamino)-pyridine-3-sulfonic acid [1 (S)-[4- (2-fluoro-ethyl)-piperidine- 1 -carbonyl]-2-(4- fluoro-phenyl)-ethyl]-amide Examples 6a to 6ak, 6α and 6cj omit the final hydrogenation step 6(e) of

Example 6

Example 6al requires further elaboration of the aminopyπdine substituent by alkylation with bromo-acetic aαd tert.-butyl ester followed by reduction (as the last step of Example 5)

Example 6am is isolated as a by-product in the preparation of Example 6al

Example 6an is produced by aαdolytic deprotection of Example 6al

Examples 6ao and 6ap require saponification as the last step

Examples 6aq to 6bu require catalytic hydrogenation as the last step (as

Examples 2 or 5)

Example 6bb is a 60:40 mixture of diastereomers (by hplc analysis)

Example 6bc is an 80.20 mixture of diastereomers (by hplc analysis)

Example 6bv is prepared as Examples 6aq to 6bu followed by a saponification step

Example 6bw is obtained by the treatment of Example 6av with propionyl chloride

Examples 6bx is obtained by treatment of Example 6cd with ethyl isocyanate

Example 6by requires aαdolytic deprotection of the tert.-butoxycaΦonyl precursor

Example 6bz is obtained after treament of the appropπate precursor with ethyl isocyanate followed by catalytic hydrogenation (as the last step of Example 5)

Examples 6ca and 6cb are obtained by a final saponification step

Examples 6cd to 6cf require a final hydrogenation step

Example eg is obtained by acetylation of the appropπate precursor

Example ch is obtained by catalytic reduction of Example 6cg

EXAMPLE 7

a) Analogously as described for Example 1(c) but using 3-(4-nιtro-phenyl)- 2(S)-tert-butoxycarbonylamino-propionic acid in place of 2(S)- benzyloxycaΦonylamιno-3-benzothιazol-2-yl-propιomc acid is prepared {2-(4- nitro-phenyl)-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-caΦonyl]-ethyl}-caΦamic add tert.-butyl ester. This is catalytically reduced as described for Example 4(e) to give {1(S)-(4-amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyr}- caΦamic add tert-butyl ester.

b) A mixture of {1(S)-(4-amino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethyl}-carbamic acid tert.-butyl ester (2g), titanium tetra-isopropoxide (2ml) and benzaldehyde (0.85ml) is stirred at room temperature for 2 hours and ethanol (20ml) is added. Sodium cyanoborohydride (1g) is added and the mixture is stirred at room temperature for 16 hours. Water (20ml) is added and solids removed by filtration. The filtrate is diluted with ethyl acetate (100ml), the organic layer is separated, washed with water (50ml), dried (MgSO4) and the solvent evaporated to give a residue which is purified by flash chromatography on a column of silicagel using hexane:ethyl acetate (1 :1 , by vol.) as eluant to give {1(S)-(4-benzylamino-benzyl)-2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert.-butyl ester as a yellow foam.

c) {1 (S)-(4-Benzylamino-benzyl)-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethyl}-caΦamic acid tert.-butyl ester (1.51g) is dissolved in acetonitrile (20ml) and aqueous fomaldehyde (37% w/v, 1.5ml) and sodium cyanoborohydride (615mg) are added followed by glacial acetic acid (1ml). The mixture is stirred at room temperature for 1 hour, further portions of aqueous fomaldehyde (37% w/v, 1.5ml) and sodium cyanoborohydride (615mg) are added and the mixture is stirred for a further 30 minutes. The mixture is extracted with ether (50ml). The extract is washed with aqueous sodium hydroxide (M, 25ml), dried (MgSO4) and evaporated to give (3-{1(S)- [4-(benzyl-methyl-amino)-benzyl]-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethyisulfamoyl}-pyridin-4-yl)-caΦamic add tert.-butyl ester as a yellow oil which is deprotected as described for Example 2(b) to give 2(S)-amino-3-[4- (benzyl-methyl-amino)-phenyl]-1-[4-(2-fluoro-ethyl)-piperidin-1-yl]-propan-1- one hydrochloride as a white foam.

d) Analogously as described for Example 1(f-g), 2(S)-amino-3-[4-(benzyl- methyl-amino)-phenyl]-1-[4-(2-fluoro-ethyl)-piperidin-1-yl]-propan-1-one hydrochloride is converted to 4-(1(S)-hydroxymethyl-2-phenyl-ethylamino)- pyridine-3-sulf onic add {1 (S)-[4-(benzyl-methyl-amino)-benzyl]-2-[4-(2-f luoro- ethyl)-piperidin-1-yl]-2-oxo-ethyr}-amide. The product is isolated by flash chromatography on a column of silicagel using dichloromethane:methanol (25:1, by vol.) as eluant.

e) 4-(1 (S)-Hydroxymethyl-2-phenyl-ethylamino)-pyridine-3-sulfonic acid

{1 (S)-[4-(benzyl-methyl-amino)-benzyl]-2-[4-(2-fluoro-ethyl)-piperidin- 1 -yl]-2- oxo-ethyl}-amide (750mg) is dissolved in ethanol (25ml) and the mixture is hydrogenated (1 bar, 20°C, 120 hours) in the presence of 10% palladium on charcoal (100mg). After removal of catalyst by filtration and of solvent by rotary evaporation, the residue is purified by flash chromatography on a column of silicagel using dichloromethane: methanol (20:1, by vol.) as eluant to give 4-(1(S)-hydroxymethyl-2-phenyl-ethylamino)-pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-1 (S)-(4-methylamino-benzyl)-2-oxo-ethyl]- amide as a white solid. [M+H]⁺ = 598.3.

The following compounds are prepared similariy, by pre-assembiy of the amino acid component (steps a-c) before final assembly, analogous to steps d and e (where appropriate):

Example Structure [M+H]⁺ NMR

7a N-(4-{3-[4-(2-Fluoro-ethyl)-piperidin-1-yl]-2(S)-[4- 626.3 1H, 13C

(1(S)-hydroxymethyl-2-phenyl-ethylamino)- pyridine-3-sulfonylamino]-3-oxo-propyl}-phenyl)- acetamide

b 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 612.2 1 H, 13C pyridine-3-sulfonic add {1 (S)-(4-ethylamino- benzyl)-2-[4-(2-fluoro-ethyl)-piperidin- 1 -yl]-2- oxo-ethyl}-amide

c 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 612.1 1 H, 130 pyridine-3-sulfonic acid [2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-1(S)-(4-formylamiho-benzyl)-2- oxo-ethyl]-amide

d 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 582.8 1 H pyridine-3-sulfonic add {1 (S)-benzyl-2-[4-(2- fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-methyl- amide

e 4-(1(S)-Hydroxymethyl-2-phenyl-ethylamino)- 579.8 1 H, 130 pyridine-3-sulfonic acid [2-(4-ethyl-piperidin-1- yl)-1 (S)-(4-methylamino-benzyl)-2-oxo-ethyl]- amide

f 4-[1(S)-Hydroxymethyt-2-(4-methoxy-pheπyl)- 609.7 1 H, 130 ethylamino]-pyridine-3-sulfonic acid [2-(4-ethyl- piperidin-1-yl)-1(S)-(4-methylamino-benzyl)-2- oxo-ethyl]-amide

g 4-[2-(3,4-Dimethoxy-ρhenyl)-1(S)- 640 1H, 130 hydroxymethyl-ethylamino]-pyridine-3-sulfonic add [2-(4-ethyl-piperidin-1-yl)-1(S)-(4- methylamιno-benzyl)-2-oxo-ethyl]-amιde

h 4-[2-(3,4-Dimethoxy-phenyl)-1- 658.5 1 H, 130

(S)hydroxymethyl-ethylamino]-pyπdine-3- sulfonic add [2-[4-(2-fluoro-ethyl)-pipeπdιn-1-yl]- 1(S)-(4-methylamιno-benzyl)-2-oxo-ethyl]-amιde

i 4-[1(S)-Hydroxymethyl-2-(4-methoxy-phenyl)- 628 2 1 H, 13C ethylamιno]-pyπdιne-3-sulfonιc add [2-[4-(2- fluoro-ethyl)-piperidιn-1-yl]-1(S)-(4-methylamιno- benzyl)-2-oxo-ethyl]-amιde

j 4-(2-Cydohexyl-1 (S)-hydroxymethyl- 604 4 1 H, 130 ethylamιno)-pyπdιne-3-sulfonιc aαd [2-[4-(2- fluoro-ethyl)-pιpeπdιn-1 -yl]-1 (S)-(4-methylamιno- benzyl)-2-oxo-ethyl]-amιde

EXAMPLE 8

Determination of the potency of the compounds

Kj value.

The compounds are analysed for their effect on the human α-thrombin- catalysed hydrolysis of the substrate Kabi S-2238 (Kabi Vitrum (UK) Ltd). The K_m and K_p values are derived from a Lineweaver-Burk plot of data, from which is calculated the K, value for the inhibitors The potency of compounds with respect to human α-thrombin is expressed as their kinetic inhibition constant (K,). Duplicate series of reaction mixtures are prepared comprising chromogenic substrate S-2238 (Kabi Vitrum) in Tris/HCI buffer (0.05M, pH 8.4) with a range of concentrations of substrate from 3.125μM to 100μM. The solutions are brought to 37°C in a thermostatically regulated heating block. Into one of the sets of duplicates is added inhibitor dissolved in a compatible vehide (water, methanol or DMSO) to give a final concentration close to the expected Kι, and into the second series is added an equivalent volume of the vehicle alone. The reactions are started by the addition of human α- thrombin (Sigma, T-8885) to give a final activity of 0.0625 NIH units/ml. Following mixing by inversion, the initial reaction rate (as change in absoΦance per minute) is measured using a Perkin Elmer Lambda 5 spectrophotometer (fitted with a cuvette holder thermostatted at 37°C) at 405nm over a period of 1 minute during which time the rate is linear and showing no signs of substrate depletion.

APTT value:

Freshly collected blood is immediately anticoagulated by mixing with one- tenth volume of trisodium citrate solution (3.8% w/v in distilled water). The blood is centrifuged at 1300 x g for 20 minutes to obtain platelet-poor plasma.

Aliquots of plasma are treated with solutions of experimental compound or vehide alone to give a range of concentrations from 0 to approximately 150μM. The APTTs of the treated plasma samples are determined using the standard method on the Instrumentation Laboratory ACL 300R coagulometer. The principle of the assay is that citrated plasma (50μl) is activated by incubating for 5 minutes at 37°C with bovine cephalin reagent (Instrumentation Laboratory (UK) Ltd, APTT (Ellagic Acid) Test Kit, 50μl), before initiating coagulation by the addition of calcium chloride solution (20mM, 50μl). The time taken for coagulation of the plasma to occur is measured automatically by the Instrumentation Laboratory ACL 300R coagulometer. The concentration of each compound required to double the

APTT of the plasma is determined from a graph of concentration of experimental compound vs APTT.

Table Potency (Kj and APTT) against human thrombin

EXAMPLE 9

Using active substances as described in any of the foregoing Examples, the following dosage forms are made.

Tablets suitable for oral administration.

Tablets containing the ingredients indicated below may be prepared by conventional techniques.

Amount per Tablet

Ingredient (mg)

Active substance 250 Lactose 140

Com starch 35

Talcum 20

Magnesium stearate 5

Total 450 mg

EXAMPLE 10

Capsules for oral administration

Capsules of the below are made up by thoroughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture

Amount per Capsule

Ingredient (mg)

Active substance 250 Lactose 250

Total 500 mg

EXAMPLE 11

The following ingredients are dissolved in water for intravenous perfusion and the resulting solution is then sterilized

Ingredient (mg)

Active substance 0.25

Buffer system as desired

Glucose 25

Distilled water 500

Claims

Claims

1. A compound of the general formula I

in which Y is a primary or secondary amino group; R₂ is the residue of a natural or synthetic amino acid; R₃ is hydrogen or a Cι-C_β alkyl chain which may be substituted by hydroxy or halogen; and X is (CH₂)_π where n is 1 , 2, or 3, or is CH₂N or represents a fused phenyl ring which is optionally substituted by one or two methoxy groups or a salt thereof.

2. A compound as claimed in claim 1 in which Y has the formula

R in which A and R are absent or A is a methylene or ethylene group, and R is hydrogen, halogen, azido, COORβ where R_β is H or alkyl, OR₉ where R₉ is H, alkyl, optionally substituted hydroxyalkyl, optionally substituted caΦoxyalkyI, optionally substituted amidoalkyl, SO₂ alkyl, SO₂ aryl, or NRioRn where Rio and Rn are independently H, alkyl which is optionally substituted and/or optionally interrupted by O or is CH₃S0₂, or together with the nitrogen atom form an optionally substituted ring which may contain another hetero atom or R is SRι₂ where Rι₂ is hydrogen or hydroxyalkyl; B is CH or is absent provided that when B is absent, A and R are also absent; Ri is hydrogen, alkyl, alkyl optionally substituted and/or optionally interrupted by O, S, carboxyl aminocarbonyi, or carbonylamino or is an optionally substituted phenyl ring or a phenyl ring containing one or more heteroatoms or a cydohexane or bicydic ring containing one or more hetero atoms; m is 0, 1 or 2 and when m is 1 and R is H, A may form a cyclopropane ring with the C atom to which Ri is attached.

3. A compound as claimed in claim 2 in which R₁₀ and R_{1 t} represent alkyl, alkyl optionally substituted by OH, COORβ where R_β is H or alkyl, caΦonyl or amide groups or by a heterocydic ring.

4. A compound as claimed in claim 2 or 3 in which Ri is an alkyl group substituted by OH, substituted hydroxyl, caΦoxyl, caΦoxyalkyI, phenyl or substituted amino.

5. A compound as claimed in claim 2 or 3 in which Ri is a phenyl ring substituted by one or more halogen or alkyl groups or one or more groups OR₄. SR₅, NR₆R₇ or COORβ where each of R to R₈ is H or alkyl or NR₆R? is NO₂.

6. A compound as claimed in any one of claims 2 to 5 in which R is selected from H, F. CI, N₃, OH, OCH₃. OSO₂CH₃, OCH₂CH₂OH and its 2-pyranyl ether, OCH_∑COOH and its tert.-butyl ester, OCH₂CON(CH₃)₂, OCH₂CONH(CH₂)₂OH, the corresponding moφholide OCH₂COMθφh, COOH and its methyl and tert.-butyl esters, SH, S(CH₂)₂ OH, S(CH₂)₃ OH, NH₂, NHCH₃, NHC₂H₅, N(CH₃)C₂H₅, NHC₃H₇(n), NHC₄H₉, NHCH₂CH₂OH, NHCONH₂, NHCONHC₂H₅, NHCH₂CH₂OCH₃. N(CH₂CH₂OCH₃)₂, NHCOCH₃, N(CH₃)CH₂COOH, NHCH₂COOH and its tert.-butyl ester, NHCH₂ pyridyl, N(CH₃)₂, N(C₂H₅)₂, pyrrolidinyl, piperidinyl, 4-hydroxypiperidinyl, moφholinyl and thiomoφholinyl.

7 A compound as claimed in any preceding claim in which Ri is deπved from optionally πng-substituted phenylaianines, tryptophans and pyπdylalanines.

8. A compound as daimed in any one of daims 2 to 7 in which the group Rι-(CH₂)_m is n-propyl, n-butyl, n-pentyl, iso-butyl, iso-pentyl, 5-hydroxy- pentyl, caΦoxylethyl, 4-phenylbutyl, n-butylcaΦamoylethyl, 2-indanyl, 4- methylbenzyl, 2-amιnobenzyl, 4-cart oxybenzyl and its methyl ester, 2- pyπdylmethyl, phenylethyl, 4-hydroxyphenylethyl and its methyl ether, 2- ammophenylethyl, caΦoxyundecyl or hydroxyethyloxyethyl

9. A compound as claimed in any preceding claim in which R₂ is deπved from the ammo acids phenylalanine, tyrosine, dopa and its ethers such as the methyienedioxy ether, p-aminophenylalanine, p-nitrophenylalanine, naphthylalanine, benzothiazolylalanine, thiazolylalanine, cydohexylalanine, the pyridylalanines, tryptophan, and fused 6/5 membered ring systems linked through the 6-membered πng and where the 5-membered πng contains one or more hetero atoms.

10. A compound as claimed in any preceding daim in which the group R₃ has 2 or 3 caφon atoms and is optionally terminally substituted by hydroxy, fluoπne or chloπne.

11. A compound as claimed in any one of claims, 2 to 10 in which A-R is present, m is 1, A is -CHr and X is (CH₂)₂.

12. A compound as claimed in any preceding claim which has the (S) configuration at each of the chiral centres.

13. A process for producing a compound of formula I as defined in claim 1 which compπses reacting 4-chloropyridιne-3-sulfonyl chloride with an aminoadd of formula

CH-

^R2 where X is -OH, protected OH or

and then reacting the resulting product with an amine of the formula

YH and finally, if necessary, reacting with a base of the formula

14. A pharmaceutical composition comprising a compound of fonnula I as defined in daim 1 together with a pharmaceutically acceptable carrier or diluent.

15. A compound of formula I as defined in claim 1 substantially as hereinbefore described with reference to any one of the foregoing Examples.