GB2312674A - Tetrahydroquinoline inhibitors of trypsin and thrombin - Google Patents

Abstract

Compounds of the general formula I in which A and B are hydrogen, a C 1 -C 5 alkyl which may be interrupted by one or more oxygen atoms, C 1 -C 5 alkenyl, alkoxyalkyl, hydroxyalkyl, alkylthioalkyl, alkylamino, dialkylamino or trialkylamino, or together form a methylene group, or together with the carbon atom to which they are attached form a C 3 -C 7 carbocylic ring; and C is a group -R-X in which R is a C 1 -C 4 alkylene group optionally interrupted by oxygen or is a direct bond and X is an aminocarbonyl, carbonylamino, sulfonylamino, amino, azido or heterocyclic alkyl, or salts thereof are inhibitors of trypsin and thrombin. Novel intermediates have the formula

Description

New Compounds The present invention relates to new compounds which have activity as inhibitors of trypsin and thrombin.

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

in which A and B are hydrogen, a C1-C5 alkyl which may be interrupted by one or more oxygen atoms, C,-Cs alkenyl, alkoxyalkyl, hydroxyalkyl, alkylthioalkyl, alkylamino, dialkylamino or trialkylamino, or together form a methylene group, or together with the carbon atom to which they are attached form a C3-C7 carbocylic ring; and C is a group -R-X in which R is a C1-C4 alkylene group optionally interrupted by oxygen or is a direct bond and X is an aminocarbonyl, carbonylamino, sulfonylamino, amino, azido or heterocyclic alkyl, or a salt thereof.

As aminocarbonyl X may have the formula -CONR1R2 in which R' is hydrogen, C1-C4 alkyl, or C-C4 hydroxyalkyl wherein the alkyl groups are optionally interrupted by oxygen, R2 is hydrogen, C1-C4 alkyl, hydroxy, C1-C4 hydroxyalkyl optionally interrupted by oxygen, or (CqH2q)-Q where q is 1 to 4 and Q is COOR4 where R4 is hydrogen, Ci- C4 alkyl or CONH2 and CqH is optionally substituted by hydroxy or interrupted by oxygen, or R2is an optionally substituted 5 or 6 membered heterocyclic ring or heterocyclic alkyl group, or R1 and R2 together with the nitrogen atom to which they are bound form an optionally substituted 5 or 6 membered heterocyclic ring.

As carbonylamino, X may have the formula -NR'COR3 in which R' is as defined above and R3 is C1-C4 alkyl optionally interrupted by oxygen, C1-C4 alkoxy, CrC,O aralkoxy, C1-C4 hydroxyalkyl, CrC5 carboxyalkyl, C2-Cs arnidoalkyl, a 5 or 6 membered heterocyclic ring, or NR5R8 where R5 and R8 are hydrogen, C1-c4 alkyl, C,-C4 aminoalkyl, C2-C5 carboxyalkyl, C,-C4 hydroxyalkyl or a 5 or 6 membered heterocyclic ring.

Preferably A and B are hydrogen or methyl.

Preferably R is an ethylene radical.

As a sulfonylamino group X may have the formula -NHS02 R7 in which R7 is C1-C4 alkyl, aryl, or heterocyclic alkyl.

When X contains a heterocyclic ring it may contain one or more hetero atoms which may be nitrogen, oxygen and/or sulfur, e.g. pyrrolidyl, piperidyl, piperazinyl, morpholyl or thiazolyl.

When a heterocyclic ring in X is substituted, suitable substituents include alkyl groups, hydroxy, carboxyl, hydroxyalkyl, carboxyalkyl alkylcarboxy, alkylcarboxyalkyl, or an aminocarbonyl group such as those of the formula -CONR'R2 defined above.

It should be noted that the carbon atom between NH and 0=0 in formula I gives rise to stereoisomers. The present invention includes the individual stereoisomers as well as mixtures. Preferably the compounds have the S configuration.

The compounds of the invention can be considered as being in three parts, an arylsulfonyl moiety ArSO2 which is

an aminoacid moiety Aa which is

and a base which is

In the arylsulfonyl moiety Cl represents C or a precursor of C.

The compounds of the invention may be made by various processes as outlined in Methods A to C below.

In these schemes below, A represents ArS02, B represents the aminoacid Aa and C represents the base Svnthetic Schemes Method A: (C#B-C#A-B-C) Base + N-protected aminoacid

coupling N-protected aminoacyl-base

deprotectio n aminoacyl-base

i) coupling

ii) deprotection (if needed) Arylsulfonyl-aminoacyl-base Method B: (BoA-BoA-B-C) Arylsulfonyl chloride + aminoacid (derivative)

coupling Arylsulfonyl-aminoacid (derivative)

deprotection (if needed) Arylsulfonyl-aminoacid

i) coupling

ii) deprotection (if needed) Arylsulfonyl-aminoacyl-base Method C Arylsulfonyl(l)-aminoacyl-base (by method A or B)

i) modification or aryl group to produce C

ii) deprotection (if needed) Arylsulfonyl(2)-aminoacyl-base In a first process compounds of formula I are prepared by reaction of aminoacyl amides of formula V HAa base (V) wherein Aa and base have their previous significance with an arylsulfonic acid derivative of formula VI ArSO2W (Vl) where W is OH or preferably halogen especially Cl or Br and where the compounds of formula V and Vl may be optionally protected and/or where the residue ArSO2 comprises a partially hydrogenated aromatic or heterocyclic system the compounds of formula VI may contain hydrogentable double bonds. The reaction of compounds of formula V with arylsulfonyl derivatives VI is carried out for instance under conditions known for introducing arylsulfonyl groups onto amino substituted compounds. In the above formulae, protected species are typically protected on the a-amino group, by benzyloxycarbonyl or t-butoxycarbonyl.

For instance compounds of formula I may be prepared by the condensation of an aminoacyl amide V with a substantially equimolar amount of an arylsulfonyl halide Vp preferably a chloride, to give a protected intermediate which yields the product I on deprotection. 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 morpholine or a solution of an inorganic base e.g. sodium hydroxide or potassium carbonate, at a temperature of OOC 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 hydrocarbons, DMF, benzene-diethyl ether, diethyl ether-water and dioxan-water.

The compounds of formula V may be prepared 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 reacfions 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 amide compounds of formula V starting materials required for the condensation reaction can be prepared by protecting the amino group of the amino acid via acetylation, formylation, phthaloylation, trifluroacetylation, p methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, butyoxycarbonylation, arylsulfonylation, or tritylation and then condensing the formed Na-substituted amino acid with the base to give a protected form of V 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 hydroxysuccininide, hydroxybenztriazole, diethyl phosphite or the like, and thereafter selectively removing the protective groups to give a compound of formula V.

In a second process, compounds of formula I may be prepared by reaction of arylsulfonyl amino acid compounds of formula Vll, wherein ArSO2 has its previous significance, with the base ArSO2AaOH (Vll) and where the compound of formulae Vll and the base are optionally protected.

Where the residue ArSO2 in Compound I comprises a partially hydrogenated aromatic or heterocyclic system, the compound VII may contain hydrogenatable double bonds.

The reaction of a compound of formula VII with the base is carried out for instance under reaction conditions known for coupling amino acids to form peptides and according to methods described in the literature (Houben Weyl, Methoden Der Organischen Chemie, Vol. 15, Parts 1 and 2).

In the above formuiae, protected species are typically protected on a a-amino groups by benzyloxycarbonyl or t-butoxycarbonyl.

For instance the compounds of formula I may be prepared by the condensation of an N"-arylsulfonyl aminoacyl halide, preferably a chloride, a mixed anhydride, or a similar activated species derived in situ from Ngarylsulfonyl amino acid VII with at least an equimolar amount of the base. The condensation reaction can be carried 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 critical and may vary from about 5 to 100 times the weight of the Na- arylsulfonyl amino acid (VI). In the other cases the activating principle such as diethyl phosphite may be the solvent.

When the activated species is an Nsarylsulphonyl aminoacyl halide it may be prepared by reacting an Nsarylsuifonyl amino acid VII with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or phosphorus tribomide. The halogenation may be carried out with or without an added solvent. The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxan. Preferred reaction temperatures are in the range of -100C to room temperature. The reaction time is not critical, but varies with the halogenating agent and reaction temperature. In general, a period of 15 minutes to 5 hours is operable.

Altematively compounds of formula I may be prepared by reaction of Nsarylsulfonyi.

amino acid of formula VII with the base in the presence of condensing agent such as a carbodiimide, for instance dicyclohexyl-carbodiimide in the presence or absence of an activating species such as hydroxybenzotriazole 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, triethylamine, N-methylmorpholine, or pyridine or an inorganic base such as sodium hydroxide or potassium carbonate. The condensation reaction may be carried out at a temperature between -100 and the boiling point of the solvent. Preferred condensation reaction temperatures are in the range from -10 G to room temperature. The reaction time is not critical. In general, a period of from 5 minutes to 10 hours is operable.

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 -100C to 1000C, 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 1, which can easily be converted to a free amide by neutralisation. When the protected compound of formula I contains the benzoxycarbonyl protection group the removal is readily accomplished by hydrogenolysis. At the same time any benzyl ester moiety is converted to the carboxyl 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 OOC 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 watermethanol, or may be chromatographed on silica gel, ion-exclusion gels or reversephase liquid chromatography supports.

In those cases where the initial product of formula I contains a protected carboxylic acid or alcohol, it is well recognised in the art that the carboxylic 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.

Where the compound of formula I obtained as described above contains a precursor of C rather than C itself the precursor Cl may contain a free carboxylic acid group, hydroxyl group or amino group. These may then be reacted with a base or acylating agent for instance by using the following methods: Method 1 - urea formation from acids

Method 2 - amide formation from acid intermediates using coupling reagents R-COOH + R1 R2NH + coupling agent + additive + base

R{:ONR1 RF R1 ,R2 may be a protected base :NBoc which can be acidolytically deprotected to give a base :NH, or an ester -COOR which can be saponified with alkali to give the carboxylic acid -COOH. These bases or acids generated can be derivatised further.

Also, acids can be derivatised to esters by standard methods such as the use of a condensing agent such as DCC with the addition of a base such as DMAP and an additive such as HOBt.

Method 3 - amide formation using acyl chloride intermediates

Method 4 - conversion of alcohols to urethanes

Method 5 - conversion of alcohols to bases

Method 6 - acylations or sulfonylations of bases

Method 7 - urea formation from amines (1)

Method 8 - urea formation from amines (2)

Method 9 - amide formation from amine intermediates using coupling reagents

RNH2 + R3COOH + coupling agent + base > RNHCoR3 R1 may contain a protected amino function or a carboxylic acid which can be appropriately deprotected to give the resulting amine or acid.

Compounds of formula Vlil are new compounds and form part of the invention:

where A, B and C are as defined above.

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 carboxyl 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 carboxylic acid with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenylamine, N,N'4ibenzylethylenediamine, N-ethylpiperidine or the like.

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

Compounds of formula VII may be prepared by reaction of the amino acid which may be optionally protected with an aryl sulfonic acid derivative of formula VI defined above in the presence of a base. The reaction is carried out under conditions well known to those skilled in the art, generally in an inert solvent and in the presence of an excess of an organic or inorganic base as hereinbefore described and at a temperature of OOC to the boiling point of the solvent.

Compounds of formula VI where W is a halogen may be prepared by methods described in the literature (Houben Weyl, Methoden Der Organischen Chemie Vol IX).

For instance the sulfonyl halides may be prepared from the corresponding sulfonic acids of formula VI where W is a hydroxyl group or a corresponding alkali or alkaline earth salt or a similar salt by treatment with a halogenating agent in the presence or absence of a solvent and optionally at elevated temperature, and with applied ultrasound.

Examples of suitable halogenating agents include phosphorus halides such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide and phosphorus oxychloride; phosgene, benzotrichloride, thionyl chloride, chlorosulfonic acid, sulfur dichloride, sulfur and chlorine, chlorine and fluorosulfonic acid.

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

The reaction is conveniently carried out between -100C 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.

Arylsulfonyl chlorides may also be prepared by chlorosulfonylation of aromatic hydrocarbons. The arylsulfonyl halide can be purified by recrystallisation from a suitable solvent such as hexane, benzene or the like.

Altematively, sulfonyl halides of formula VI may be prepared from the corresponding parent aromatic compound of formula IX ArH (IX) by halo sulfonation according to methods well known in the art using for instance chlorosulfonic acid.

Compounds of formula Vllla

wherein A, B and Cl have their previous significance may be prepared by the sequence of reactions shown in Scheme 1. Scheme 1

A COOH Cl 1 COO C1 H2M 0 T B)$mI MNiCl N sulfonabon B/ < .CO BI chlorination Nt H S02CI Sulfonyl halides of formula VI may also be prepared by the following schemes 2 and 3.

Scheme 2

A alkylatinf H I 0' A H B$I N H H o1efi:f:;Poud < C1 Pd cat H sulfonation A C1 chlorination > H NH S02C1 Scheme 3

Br NC1 Br NC Br $2NN ANHN B Grignard A I oBM H ) then as in Scheme 2 Compounds of formula Vl where W is a hydroxy group may be prepared by methods described in the literature (Houben Weyl, Methoden Der Organishen Chemie Vol. lox).

For instance by sulfonation of an aromatic compound ArH.

Suitable reagents for sulfonation include sulfuric acid, oleum, sulfur trioxide and complexes of sulfur trioxide, for instance the pyridine complex, acid suifates such as potassium hydrogen sulfate, and chlorosulfonic acid. The sulfonation may be carried out with or without the presence of a catalyst. Catalysts may include metal salts, such as mercury salts or acids such as hydrogen fluoride or Lewis acids such as boron trifluoride. The reaction may be carried out in the presence or absence of a solvent inert under the reaction conditions and at a temperature between OOC and the boiling point of the solvent.

The compounds of the formula I provide interesting compounds which contain potent and morally bioavailable inhibitors of serine proteases, especially thrombin and trypsin.

The compounds of the present invention are useful in compositions, combinations and methods for the treatment and prophylaxis of various diseases attributed to thrombinmediated 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 cardiological 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, an isolated 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 administration of 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/lila 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 wilt be formulated using adjuvants and diluents suitable for the desired method of administration. Thus the compositions may be administered intravenously or intraarterially as bolus or by continued infusion, intramuscularly - including paravertebraty and periarticularly - subcutaneously, intracutaneously, intra-articularly, intrasynovially, 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 andlor 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, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salts andlor 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, croscarmellose, agar, alginic 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, emuisions, 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, hydroxyethylcellulose, 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 warmblooded animal (mammal), the body weight,

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-corporeal 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, stentsitubing, membranes and catheters, Methods for coating these devices are known to those of skill in the art. These include chemical cross-linking or physical adsorption 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 extracorporeal 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 extracorporeally 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 0.01 mg/60ml of extracorporeal blood to 5mg/60ml of extracorporeal 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 BTMA.IC12 Benzyltrimethylammonium iodine dichloride DAST Diethylamino sulfur trifluoride DCC Dicyclohexylcarbodiimide DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMID 1 ,3-Dimethyl-2-imidazolidinone DMS Dimethyl sulfide DMSO Dimethyl sulfoxide HOBt Benzotriazol-1 -ol Huenig Base Ethyldiisopropylamine Ishikawa reagent Diethyl-(1 , 1 ,2,3,3,3-hexafluoro-propyl)-amine Lawesson's reagent p-Methoxyphenylthionophosphine sulphide dimer LDA Lithium diisopropylamide NMM N-Methyl morpholine PyBOP Benzotriazol-1 -yloxy-tris-pyrrolidinophosphonium hexafluorophosphate TBAF Tetrabutylammonium fluoride TBTU 2-(1 H-Benzotriazol-1 -yl)-1 ,1 ,3,3,-tetramethyluronium tetrafluoroborate THF Tetrahydrofuran TPTU O-(1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate Reagent 1 a) Method 1 i) 4(2-Hydroxy-ethyl)-piperidine-1-carboxylic 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 ffen 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 ether:hexane (1:1, by vol.) as eluant. Appropriate fractions are combined and the solvent removed to give 4-(2-fluoro-ethyl)-piperidine-l -carboxylic acid tert.-butyl ester.

ii) S(2-Fluoro-ethyl)-piperidine-1 carboxylic 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 $(2-fluoro-ethyi3- piperidine hydrochloride which is held in vacuo (NaOH pellets).

Method 2 4(2-Hydroxy-ethyl)-pperidine-1 -carboxylic acid tert.-butyl ester (6.539) is dissolved in dichloromethane (29ml) and the solution is heated to 800C at 2 bar (autoclave) Ishikawa reagent (7.299) 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 800C. The cooled mixture is washed with portions (2x20ml) of 50% brine and 50% brine buffered to pH4-5. The organic phase is dried (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)-piperidine-1-carboxylic acid tert.-butyl ester as a light yellow oil. This is converted to 4-(2-fluoro-ethyl)-piperidine hydrochloride as described in Method 1 above.

Method 3 i) [4-(2-Hydroxy-ethyi)-piperidin-1-yl]-phenyl-methanone (31.59) is dissolved in dichloromethane (200ml) and pyridine (10.9ml) and methanesulfonyl chloride (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 (MgSO4) and evaporated to give methanesulfonic acid 2-(1 -benzoyl-piperidin-4- yl)-ethyl ester as a waxy solid which is sufficiently pure for use without further purification.

ii) Methanesulfonic acid 2-(1 benzoyl-piperidinA-yl)-ethyl ester (41.59) is dissolved in acetonitrile (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-l -yl]-phenyl-methanone as an oil.

iii) [4(2-Fluoro-ethyl)-piperidin-1 -yl]-phenyl-methanone (17.1 g) 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 extrated 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.

450C/3mm.

b) 2(S)lBenzyloxycarbonylamino-3-benzothiazol-2-yl-propionic acid benzyl ester (lOg) is dissolved in THF (60ml) and water (20ml), lithium hydroxide monohydrate (1.859) and aqueous hydrogen peroxide (27.5%, 16ml) are added. The solution is kept at 20'C for 1 hour and sodium sulfite (179) in water (50ml) is added slowly to the stirred mixture in an ice-bath. The solution is acidified to pH4 (conc. 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.- butylmethylether.

c) 4-(2-Fluoro-ethyl)-piperidine hydrochloride (1.27g). 2(S)-benzyloxy-carbonylamin 3-benzothiazol-2-yl-propionic acid (2.709) and PyBOP (3.939) are dissolved in dry dichioromethane (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 its 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)-benzyloxycarbonyl-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)-benzyloxycarbonylamino-3-benzothiazol-2-yl-1-[4-(2-fluoro- ethyl)-piperidin-1-yl]-propan-1-one (1.649) 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.-butylmethyi ether and triturated with diethyl ether to give pure 2(S)-amino-3-benzothiazol-2-yl -[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 -14-(2-fluoro-ethyl)-piperidin-t -yli-propan- 1-one dihydrobromide (16.49) 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. 21 ml) with vigorous stirring. The organic layer is separated and the aqueous phase is extracted with ethyl acetate (2x100ml). The combined organic extracts are dried (MgSO4) and evaporated to give 2(S)-amino-3-benzothiazol-2-yl-1 -[4-(2-fluoroethyl)-piperidin-1-yl]-propan-1-one as a pale brown oil.

Reagent 2 a) Dimethylmalonic acid (1.329) is dissolved in THF (1 Oml), thionyl chloride (0.88ml) is added and the mixture is heated at reflux for 2 hours and then cooled to 0 C. A solution of 4-amino-benzoic acid ethyl ester (3.379) in ether (60ml) is added dropwise between 0'C and 10'C during 60 minutes. The suspension is stirred for 1.5 hours at 0 C and then ovemight at room temperature. The suspension is extracted with portions (3x30ml) of ethyl acetate. The combined organic layers are washed with water (30ml), dried (MgSO4) and evaporated to give a brown residue which is purified by flash chromatography on a column of silicagel eluting with dichloromethane and then dichloromethane:methanol (4:1, by vol.) to give brownish crystals of 4-(2 carboxy-2-methyl-propionylamino)-benzoic acid ethyl ester.

b) Phosphorus pentoxide (1 6.79) is dissolved in methane sulphonic acid (261 ml) and the solution heated to 70 C. 4(2-Carboxy-2-methyl-propionylamino)-benzoic acid ethyl ester (58.39) is added in one portion and the solution is stirred for 24 hours at 70'C. The solution is poured into water (11) and extracted with portions (31) of ethyl acetate (2x). The combined organic layers are washed with water (2x500ml), dried (MgSO4) and evaporated. The residue is dried in vacuo (P2O5) ovemight. The brown residue is triturated with chloroform (11), the suspension is filtered and the solid washed with chloroform. This is dried ovemight in vacuo to give 3,3-dimethyl-2,4 dioxo-l ,2,3,4-tetrahydroquinoline-6-carboxylic acid as a cream solid. The residue obtained by evaporation of the mother liquor is dissolved in chloroform (250ml), hexane (21) is added and the suspension stirred, filtered and the solid washed with hexane. The filtrate is evaporated and the procedure is repeated twice. The combined crops of 3,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester are dried in vacuo.

The recovered 3,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (209) is dissolved in dichloromethane (200ml) and ethanol (15ml), DMAP (7.8 & 9) and DCC (19.4g) are added. The mixture is stirred at room temperature for 12 hours and filtered. The filtrate is washed with portions (1 OOml) of aqueous hydrochloric acid (2M, 2x), saturated aqueous sodium bicarbonate (3x) and brine, dried (MgS04) and evaporated. The residue is purified by flash chromatography on a column of silicagel using dichloromethane:ethyl acetate (9:1, by vol.) as eluate to afford 3,3 < limethyl-2,4- dioxo-1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid ethyl ester as a white solid.

c) 3,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (lOg) is dissolved in ethanol (250ml), 10% palladium on charcoal (2g) is added arfid the mixture is hydrogenated (1 bar) at room temperature for four days. After removal of the catalyst, evaporation of the filtrate affords white crystals of 3,3dimethyl-2oxo- 1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester.

Altematively: 3,3-Dimethyl-2,4-dioxo-1 ,2,3,4-tetrahydro-6-carboxylic acid ethyl ester (3.52g) is dissolved in trifluoroacetic acid (1 00ml) and trimethylsilane (5.6ml) is added.

The mixture is heated under nitrogen at 600C for 6 hours, cooled and poured cautiously into a mixture of saturated aqueous potassium carbonate (20ml) and ice (20ml). The mixture is extracted with portions (3x20ml) of ethyl acetate, the combined ectracts are washed with brine (20ml), dried (MgS04) and solvent evaporated to give 3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester as an oil which crystallises on trituration with hexane at 40C.

d) 3,3-Dimethyl-2-oxo-1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (8.2g) is dissolved in THF (450ml), Lawesson's reagent (13.429) is added and the mixture heated at reflux for 5.5 hours. The mixture is cooled and evaporated to dryness. The residue is purified by elution with chloroform from a pad (1 2x1 9cm diameter) of silicagel to give crystals which are recrystallised from chloroform:hexane to give 3,3 dimethyl-2-thioxo-1,2,3,4-tetrahydrosuinoline-6-carboxylic acid ethyl ester. Further pure product is obtained by extraction of the silica pad and by work up of the mother liquors.

Altematively: 3,3-Dimethyl-2-oxo-l ,2,3,4-tetrahydro-quinoline-6-carboxyiic acid ethyl ester (14.49) is dissolved in dioxan (418ml) and heated to 100 with vigorous stirring.

Phosphorus pentasulfide (11.89) is added and the mixture is heated for 3 hours and then cooled. The supematant liquid is collected by decantation and dried. The residue is slurried in dichloromethane (25ml) and applied to a pad (25x15cm diameter) of silicagel which is eluted with hexane:dichloromethane (1:1, by vol., 8.51) and then dichloromethane (81) to give 3,3-dimethyl-2-thioxo- 1,2,3 ,4-tetrahydro-quinoline-6- carboxylic acid ethyl ester as a solid.

e) 3,3-Dimethyl-2-thioxo- I ,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (6.259) is dissolved in THF (100ml), methyl iodide (1.629) is added and the solution cooled to 0-5'C. Potassium tert.-butoxide (2.939) is dissolved in THF (400ml) and the solution added dropwise at 0-5 C during 30 minutes. Further potassium tert.-butoxide (0.79) dissolved in THF (12ml) and methyl iodide (80pJ) are added dropwise and the mixture stirred for 150 mintues (0-5'C) until all the starting material is consumed. The mixture is poured into ice-water (21) and extracted with portions (2x250ml) of ethyl acetate. The combined organic layers are washed with portions (25ml) of brine, dried (MgS04) and evaporated to give a yellow oil which is purified by flash chromatography on a column of silicagel using dichloromethane as eluant to give 3,3dimethyl-2-methylsulfanyl-3,4-dihydro-quinoline-6-carboxylic acid ethyl ester as a yellowish oil which crystallises on storage.

f) 3,3-Dimethyl-2-methylsulfanyl-3,Sdihydro-quinOline-6-carboxylic acid ethyl ester (275mg) is dissolved in methanol (10ml) and the solution cooled to 15-C. Sodium cyanoborohydride (124.5mg) is added in one portion and aqueous hydrochloric acid in ethanol (6.8M) is added dropwise to pH 3 at a temperature of 15-20-C. The solution is stirred for 20 minutes, evaporated and the residue extracted with portions (2x20ml) of ethyl acetate. The combined extracts are washed with portions (2x20ml) of saturated aqueous sodium bicarbonate and brine, dried (MgSO4) and evaporated to give yellowish crystals which are purified by flash chromatography on a column of silicagel eluting with dichloromethane to give 3,3-dimethyl-1 ,2,3,4-tetrahydro- quinoline-6-carboxylic acid ethyl ester as white crystals.

g) 3,3-Dimethyl-2-oxo-l ,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (12.49) is dissolved in dry THF (500ml), cooled to 0 C and borane:methylsulfide complex (6.35ml) is added dropwise with stirring which is continued for 30 minutes at 0 C and then at 20'C for 16 hours. Methanol is added dropwise with caution until excess of reagent is destroyed and solvents are removed by rotary evaporation.

Portions of methanol (3x30ml) are distilled from the residue by rotary evaporation and the resulting oil is crystallised from ethyl acetate:hexane to give 3,3-dimethyl-1,2,3,4- tetrahydro-quinoline-6-carboxylic acid ethyl ester as white crystals, m.p. 79-8OC.

h) 3,3-Dimethyl-1,2,3,Stetrahydro-quinoline-6-carboxylic acid ethyl ester (3.06g) is dissolved in pyridine (120ml), pyridinelsulfurtrioxide complex (10.5g) is added and the mixture heated at reflux for 2 hours. The mixture is cooled and evaporated to dryness and the residue extracted with portions of ethyl acetate (2x1 Cml) and water (3x25rnt).

The combined water extracts are evaporated and the residue dried in vacuo ovemight. Coid aqueous hydrochloric acid (M) is added to the residue, the crystals of 6-ethoxycarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid are filtered off and washed with a little cold acid. A further crop of product is obtained from the liquors by evaporation and washing of the residue with cold acid.

i) 6-Ethoxycarbonyl-3,3-dimethyi-l ,2,3,4-tetrahydro-quinoline-8-sulfonic acid (1 .6g) is dissolved in DMlD (12ml), pyridine (0.76ml) and phosphoryl chloride (0.6ml) are added and the solution is stirred for 40 minutes. The mixture is added to ice-water (4OOrfll) and the solution extracted with portions (3x200ml) of ethyl acetate:ether (1:1, by vol).

The combined extracts are dried (MgSO4) and evaporated to give a residue which contains a little DMID. Repeat partition and work-up gives 8-chlorosulfonyl-3,3dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester as yellow crystals.

Reagent 3 Method 1 a) 2-Aminobenzonitrile (130.39) in dichloromethane (1.11) is added with stirring to a solution of potassium carbonate (152.49) in water (550ml). A solution of 2-bromo2- methyl priopionyl bromide (279.19) in dichloromethane (300ml) is added dropwise over 1 hour keeping the temperature of the mixture below 250C and the resulting emulsion is stirred vigorously for 3 hours. The organic phase is separated and the aqueous phase is washed with dichloromethane (220ml). The combined organic phases are rotary evaporated to dryness and the resulting orange crystalline mass of 2-bromo-N-(2-cyano-phenyi)-isobutyramide is dried for 16 hours in vacuo, m.p. 66 90C.

b) A solution of 2-bromo-N-(2-cyano-phenyl)-isobutyramide (296.1g) in dry THF (11) is added dropwise over 2 hours to a solution of ethyl magnesium bromide (512.9g) in dry THF (1.21) under conditions of gentle reflux. The resulting mixture is stirred and heated at reflux for 16 hours and cooled. The suspension is added with stirring to a mixture of aqueous hydrochloric acid (1.11) and crushed ice (1kg) and the mixture is stirred for 1 hour, allowing it to come to room temperature. The mixture is extracted with ethyl acetate (2x11) and the combined extracts are washed with brine (it), dried (Na2S04) and evaporated to give an orange crystalline mass which is washed by suspension in 2-methoxy-2-methyl-propane (250ml), filtration and washing with 2methoxy-2-methyl-propane (100ml). The liquors yield further product on evaporation and trituration with cold 2-methoxy-2-methyl-propane. The combined yellow crystals are dried for 16 hours at 500C to give 3,3-dimethyl-1 H-quinoline-2,4-dione, m.p. 157610C.

c) 3,3-Dimethyl-1H-quinoline-2,4-dione (1 26.5g) dissolved in dry THF (730ml) is added dropwise over 2.5 hours to an ice-cold preformed mixture of lithium aluminium hydride (76.29) and aluminium trichloride (89.29) in dry THF (1.461) and the mixture is stirred for a further 2 hours at OOC. A mixture of water (90ml) and THF (150ml) is added cautiously to the well-stirred solution under cooling, THF (150ml) is added to the thick suspension followed by aqueous sodium hydroxide (15% w/v, 90ml) and water (270ml) and the mixture is stirred at room tempertaure for 16 hours. Solids are removed by filtration and washed with THF (1.51) and the combined filtrates are evaporated to dryness. The residue is dissolved in 2-methoxy-2-methyl-propane (300ml), washed with brine (100ml), dried (Na2S04) and the solution evaporated to give crude 3,3-dimethyl-1 ,2,3,4-tetrahydroquinoline which is purified by distillation (60650C/0.4mbar) to give a light yellow liquid.

d) 3,3-Dimethyl-1 ,2,3,4-tetrahydroquinoline (93.39) is dissolved in a mixture of dichloromethane (1.651) and methanol (550ml) and cooled to 50C. BTMA.IC12 (211.39) and potassium carbonate (75.29) are added and the suspension is stirred at 50C for 1.5 hours. The solids are collected by filtration, washed with dichloromethane (250ml) and the combined filtrates dried by rotary evaporation. The residue is dissolved in a mixture of 2-methoxy-2-methyl-propane (21) and water (11), the organic phase is collected and the aqueous phase is extracted with a second portion (300ml) of the ether. The combined organic phases are washed with aqueous sodium thiosulfate (1% wh, 11), water (500ml), brine (500ml), dried (Na2S04) and the solution evaporated to a volume of 21. The solution is saturated with hydrogen chloride and the crystalline material is collected by filtration, washed with 2-methoxy-2-methyS propane (500ml) and dried in vacuo to give 6-iodo-3,3-dimethyl-1,2,3,4-tetrahydro- quinoline hydrochloride as yellow crystals, m.p. 145-70C.

e) 6-iodo-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline hydrochloride (253.3g) is stirred with dry DMF (1.251) and sodium bicarbonate (230.49) is added in portions followed by acrylic acid ethyl ester (117.79), tetrabutylammonium chloride (231 .9g) and palladium(ll)acetate (3.59). The mixture is stirred at 800C for 2 hours, cooled to room temperature and dried by rotary evaporation. The residue is shaken with 2-methoxy 2-methyl-propane (1.51) and water (500ml), solids removed by filtration and the separated aqueous phase washed with a further portion (500ml) of the ether. The combined organic phases are washed with portions (500ml) of water and brine, dried (Na2S04) and the solution evaporated to dryness to give 3-(3,3-dimethyl-1,2,3,4- tetrahydro-quinolin-6-yl)-acrylic acid ethyl ester as a light brown oil suitable for immediate use.

f) 3-(3,3-Dimethyl-1,2,3,4-tetrahydrosuinolin-6-yl)-acrylic acid ethyl ester (210g) is dissolved in ethanol (21) and hydrogenated (1 bar) in the presence of 10% palladium on charcoal (21g) for 10 hours at room temperature. Removal of the catalyst and solvent affords 3-(3,3-dimethyl-1 ,2,3,4-tetrahydroguinoiin-6-yl)-propioni acid ethyl ester which is purified by vacuum distillation (141-4 C/0.02mbar).

g) 3-(3,3-Dimethyl-1 ,2,3,4tetrahydro < luinolin-6-yl)-propionic acid ethyl ester (2069) is dissolved in DMF (21) and DMF/sulfur trioxide complex (1339) is added with stirring.

The mixture is heated to 800C with stirring for 1 hour and rotary evaporated to dryness. The re (2-ethoxycarbonyl-ethyl)-3,3-dimethyl- 1,2,3 ,tetrahydro-q uinoline8-sulfonic acid as beige crystals, m.p. 1 62-50C.

h) S(2-Ethoxycarbonyl-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid (750mg) is converted as described above for Reagent 2i to yield 3-(8-chlorosulfonyl 3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester, which crystallises on storage in vacuo.

Method 2 Analogously as described for Reagent 2 but using 3-(4-amino-phenyl)-acrylic acid ethyl ester in place of 4-aminobenzoic acid ethyl ester is prepared 3-(3,3-dimethyl-2,4 dioxo-1 ,2,3,4-tetrahydro-quinolin-6yl)-acrylic acid ethyl ester which is hydrogenated as described for Reagent 2c but using acetic acid:methanol (1:4, by vol.) in place of ethanol as solvent to afford 3-(3 ,3dimethyl-2-oxo- 1,2,3 4-tetrahydro-qu inolin-6-yl)- propionic acid ethyl ester. This is treated as described for Reagent 2d-i to yield 3-(8 chlorosulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester as a pale yellow solid identical to that obtained by Method 1 of this example.

Altematively: a) 3-(3,3-Dimethyl-2,4,-dioxo-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester (1.019) is dissolved in a mixture of THF (20ml) and ethanol (40ml) and hydrogenated (1 bar) in the presence of 10% palladium on charcoal (0.11 g) at 200C for 3 hours. After removal of catalyst and solvents, the residue is purified by flash chromatography on a column of silicagel using ethyl acetate as eluant to give 3 (4(RS)-hydroxy-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester as a colourtess oil.

b) 3-(4(RS)-Hydroxy-3,3-dimethyl-2-oxo- 1 ,2,3,4-tetrahydro-qu inolin-6-yl)-propionic acid ethyl ester (0.9g), DMAP (0.1g) and triethylamine (0.57m) are dissolved in dichloromethane (20ml) and acetic anhydride (0.32ml) is added. The solution is stirred for 3 hours, evaporated to dryness by rotary evaporation and the residue purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (7:3, by vol.) as eluant to give 3-(4(RS)-acetoxy-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro- quinolin-6-yl)-propionic acid ethyl ester as a colourless oil.

c) 3-(4(RS)-Acetoxy-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester (0.8g) is dissolved in ethanol (30ml) and palladium oxide (O.2g) is added. The mixture is hydrogenated at 200C for 3 days. Removal of catalyst and solvent gives a residue which is purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (1:1, by vol.) as eluant to give 3-(3,3-dimethyI2- oxo-l ,2,3,etetrahydro-quinolin-6yl)-propionic acid ethyl ester as a colourless oil which crystallises on storage. This is treated as described for Reagent 2d-i to yield 3 (8-chlorosulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester identical to that obtained by Method 1 of this example.

Reagent4 Analogously as described for Reagent 3 but using diethylmalonic acid in place of dimethyl masonic acid is obtained 3-(8-chlorosulfonyl-3,3-diethyl-1,2,3,4-tetrahydro- quinolin-6-yl)-propionic acid ethyl ester as a pale yellow oil.

Reagent 5 Analogously as described for Reagent 2 but using diethylmalonic acid in place of dimethylmalonic acid is prepared 8-chlorosulfonyl-3,3-diethyl-l ,2,3,4-tettahybt9- quinoline-6-carboxylic acid ethyl ester as a white solid.

Reagent 6 a) A solution of 3,4-dihydro-1 Hquinolin-2-one (11g) in dry THF (50ml) is added at 0 C to a solution of LDA in hexane (1.5M, 100ml) and a further portion (450ml) of cold, dry THF is added. The solution is allowed to warm to room temperature and is stirred for 2 hours and the solution is cooled to -780C. Ethyl iodide (6ml) is added and the stirred solution is allowed to warm to room temperature, diluted with ethyl acetate (600ml) and washed with water (2x500ml). The combined water washings are back extracted with ethyl acetate (2x1 00ml) and the combined ethyl acetate fractions are dried (MgS04) and evaporated to dryness to give 3(RS)-ethyl-3,4-dihydro-fH- quinolin-2-one as a pale yellow solid.

b) 3(RS)-Ethyl3 ,4-dihydro-l Hquinoiin-2-one (11 g) is dissolved in dry THF (200ml) and BH3.DMS complex (18.8ml) is added at OOC. The mixture is stirred at 200C for 72 hours and then heated at reflux for 2 hours. Methanol is added cautiously to quench the reaction mixture and solvents are removed by rotary evaporation. The residue is purified by chromatography on a column of silicagel which is eluted with hexane:ether (8:1, by vol.) to give 3(RS)-ethyl-l ,2,3,4-tetrahydro-quinoline as a colourless oil.

c) 3(RS)-Ethyl-1,2,3,4-tetrahydro-quinoline (59) is dissolved in dry dichloromethane (135ml) and BTMA.IC12 (10.89) is added. Calcium carbonate (49) and methanol (50ml) are added and the resultant slurry is stirred at 200C for 16 hours, diluted with dichloromethane (100ml) and washed with portions (2x100ml) of 5% (w/v) aqueous sodium bisulphite. The organic phase is dried (MgS04) and evaporated to dryness to give 3( RS)-ethyl-6-iodo-1 2,3 ,4-tetrahydro-quinoline as a colourless oil which solidifies on storage.

d) 3(RS)-Ethyl-6-iodo-1,2,3,4-tetrahydro-quinoline (7.79), acrylic acid ethyl ester (4.34ml), triethylamine (5.5ml) and tri-(ortho-tolyl)-phosphine (2.439) are dissolved in dry DMF (15ml), palladium(ll)acetate (0.69) is added and the mixture is heated at 1000C for 16 hours. Ethyl acetate (150ml) is added to the cooled solution which is washed with portions (2x200ml) of water, the organic phase is dried (MgSO4) and rotary evaporated. The residue is purified by chromatography on a column of silicagel using hexane:ether (4:1, by vol.) as eluant to afford 3-(3(RS)-ethyl-1 ,2,3,4- tetrahydro-quinolin-6-yl)-acrylic acid ethyl ester as a yellow oil.

e) 3-(3(RS)-Ethyl-1 ,2,3,4-tetrahydro-quinolinyl)-6-acrylic acid ethyl ester (3.3g) is dissolved in ethanol (100ml) and palladium on charcoal (5%, 330mg) is added. The mixture is hydrogenated at 1 bar and 200C for 5 hours. The catalyst is removed by filtration and the solution evaporated to dryness to give 3-(3(RS)-ethyl-1,2,3,4- tetrahydro-quinolin-6-yl)-propionic acid ethyl ester as a colourless oil.

f) Analogously as described for Reagent 2h-i but using 3-(3(RS)-ethyl-1 ,2,3, tetrahydro-quinolin-6-yl)-propionic acid ethyl ester in place of 3,3-dimethyl-1 2,3,4- tetrahydro-quinoline-6-carboxylic acid ethyl ester is obtained 3-(8-chlorosulfonyl 3(RS)-ethyl-l ,2,3,4-tetrahydroquinolin-6-yl)-propioni acid ethyl ester as a light yellow oil.

Reagent7 Analogously as described for Reagent 6 but using methyl iodide in place of ethyl iodide is obtained 3-(8-chlorosulfonyl-3(RS)-methyl-1,2,3,4-tetrahydro-quinolin-6-yl) propionic acid ethyl ester.

Reagent 8 Analogously as described for Reagent 6 but using propyl iodide in place of ethyl iodide is obtained 3-(8-chlorosulfonyl-3(RS)-propyl-1,2,3,4-tetrahydro-quinolin-6-yl)- propionic acid ethyl ester.

Reagent 9 Analogously as described for Reagent 6 but using isopropyl iodide in place of ethyl iodide is obtained 3-(8-chlorosulfonyl-3(RS)-isopropyl-1,2,3,4-tetrahydro-quinolin-6-yl)- propionic acid ethyl ester.

Reagent 10 Analogously as described for Reagent 6 but using isobutyl iodide in place of ethyl iodide is obtained 3-(8-chlorosulf onyl-3(RS)-isobutyl- 1 ,2,3,4-tetrahydro-quinolin-yl) propionic acid ethyl ester.

Reagent 11 Analogously as described for Reagent 6c-f but using 1 ,2,3,4-tetrahydroguinoline in place of 3(RS)-ethyl-1,2,3,4-tetrahydro-quinoline is prepared 3-(8-chlorosulfonyl- I ,2,3, tetrahydro-quinolin-6-yl)-propionic acid ethyl ester which is obtained as a yellow oil.

Reagent 12 a) 1 ,2,3,4-tetrahydroquinoline-3(RS)-carboxy acid is converted by a standard procedure using benzyl chloroformate to 3,4-dihydro-2ti -qu inoline -1 3(RS)clicarboxylic acid 1 -benzyl ester.

b) 3,4-Dihydro-2Hquinoline- 1 ,3(RS)-dicarboxyiic acid 1 -benzyl ester (6.159), PyBOP (15.569) and Huenig Base (13ml) are dissolved in dichloromethane (200ml) and the mixture is stirred for 10 minutes at 200C. N,O-Dimethylhydroxylamine hydrochloride (2.889) is added and the mixture is stirred for a further two hours. The solution is diluted with dichloromethane (200ml), washed with aqueous hydrochloric acid (2M, 200ml), dried (MgSO4) and solvent removed by rotary evaporation. The residue is purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (4:1, by vol.) as eluant to give 3(Rs)-(methoxymethylcarbamoyl)-34-dihydro-2H-quinoline- 1 -carboxylic acid benzyl ester.

c) 3(RS)-(Methoxy-methyl-carbamoyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (6.7959) is dissolved in dry THF (100ml) and methylmagnesium bromide 1.4M in THF, 21.28ml) is added. The mixture is stirred for 2 hours at 200C, water (semi) is added followed by ethyl acetate (100ml) and the solution is washed with aqueous hydrochloric acid (M, 100ml). The organic phase is dried (MgSO4) and the solvent removed by rotary evaporation to give a residue which is purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (1:3, by vol.) as eluant to give 3(RS)-acetyl-3,4 dihydro-2H-quinoline-1 -carboxylic acid benzyl ester.

d) 3(Rs)-Acetyl-374-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (5.59) is dissolved in dichloromethane (50ml) and 3-chloroperoxybenzoic acid (50%, 12.29) is added. The mixture is stirred at 200C for 24 hours, a further portion (15g) of 3-chloroperoxybenzoic acid is added and the mixture is stirred for a further 24 hours. Aqueous sodium sulfite (100 ml, 10% w/v) is added followed by dichloromethane (50ml) and the solution is stirred vigorously for 45 minutes. The mixture is washed with portions (3x10ml) of aqueous sodium sulfite (10% w/v), the organic phase dried (Mg5O4) and the solvent removed by rotary evaporation. The residue is purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (1:4, by vol.) as eluant to give 3(RS)-acetoxy-3,4dihydro-2H-quinoline-1 -carboxylic acid benzyl ester as a colourless oil.

e) 3(RS)-Acetoxy3,4-dihydro-2Hquinoline-l -carboxylic acid benzyl ester is saponified by a standard procedure (2M NaOH, 2 hours, room temperature) and 3(RS)-hydroxy-3,4dihydro-2H-quinoline-1-carboxylic acid benzyl ester is recovered by extraction with ethyl acetate. Storage of the oil obtained yields a cream solid.

f) 3(RS)-Hydroxy-3,4-dihydro-2H-quinoline-1-CarbOxylic acid benzyl ester (2.859) is dissolved in DMF (40ml) and ethyl iodide (8ml) is added. The stirred mixture is cooled to OOC and sodium hydride suspension (60% w/v, 0.89) is added. The mixture is stirred ar 20 C for 2 hours, diluted with ether (100ml) and washed with portions (2x100ml) of water.

The organic phase is dried (MgSO4) the solvent removed by rotary evaporation and the residue obtained is purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (1:5, by vol.) as eluant to give 3(RS)-ethoxy-3,4-dihydro-2H-quinoline-1- carboxylic acid benzyl ester as a colourless oil.

g) 3(RS)- Ethoxy-3,4aihydro-2Hquinoline-1 -carboxylic acid benzyl ester (2.81g) is dissolved in ethanol (150ml) and hydrogenated (1 bar) in the presence of 10% (w/w) palladium on charcoal for 5 hours at 200C to give, after removal of the catalyst and solvent, 3(RS)-ethoxy-3,4-dihydro-2H-quinoline as a colourless oil.

h) Analogously as described for Reagent 6c-f but using 3(RS)-ethoxy-1,2,3,4-tetrahydro- quinoline in place of 3(RS)-ethyl-1 ,2,3,4-tetrahydro-quinoline is prepared 3-(8- chlorosulfonyl-3(RS)-ethoxy-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester as a light yellow oil.

Reagent 13 a) (1,2,3,4-Tetrahydro-quinolin-3(RS)-yl)-methanol (1.799) is dissolved in dry THF (1 OmI) and sodium hydride dispersion (60%, 442mg) is added. The suspension is stirred at room temperature for 20 minutes, methyl iodide (0.68ml) is added and the mixture is stirred for 4 hours. Water (1ml) is added followed by ether (20ml) and the mixture is washed with water (20ml). The separated organic phase is dried (MgS04) and the solvent evaporated to give a residue which is purified by flash chromatography on a column of silicagel using hexane:ether (1:1, by vol.) as eluant to give 3(RS)-methoxymethyl-1 ,2,3,4-tetrahydro-quinoline as a colourless oil.

b) Analogously as described for Reagent 6c-f but using 3(RS)-methoxymethyl 1,2,3,4-tetrahydro-quinoline in place of 3(RS)-ethyl-1 ,2,3,4-tetrahydro-quinoline is prepared 3-(8-chlorosulfonyl-3(RS)-methoxymethyl-1,2,3,4-tetrahydro-quinolin-6-yl)propionic acid ethyl ester as a yellow oil suitable for immediate use.

Reagent 14 a) Dimethylmalonic acid (8.849) is dissolved in dry THF (100ml) under an atmosphere of nitrogen. Thionyl chloride (5.94ml) is added and the mixture is heated to reflux for 2 hours, cooled to O'C and (4-amino-phenyl)-acetic acid ethyl ester (249) in ether (300ml) is added dropwise over 1 hour with the temperature below 1 0'C. The mixture is stirred at room temperature for 2 hours and poured into water (250ml) and the solution extracted with ethyl acetate (2x250ml). The combined extracts are dried (MgSO4), the solvents evaporated and the residue of crude N-(Cethoxy- carbonylmethyl-phenyl)-2,2-dimethyl-malonamic acid is held in vacuo (NaOH pellets).

b) N-(4-Ethoxycarbonylmethyl-phenyl)-2,2-dimethYI-malonarnic acid (1 Og) and phosphorous pentoxide (5.49) are dissolved in methane sulfonic acid (75ml) and heated to 70'C with stirring for 3 hours. The reaction mixture is cooled to 20'C and iced water (400ml) is added slowly with stirring. The aqueous phase is extracted with ethyl acetate (3x300ml) and the combined extracts are dried (Mg5O4) and evaporated to a black tar which dissolved in ethyl acetate (200ml) and the solution extracted with saturated aqueous sodium bicarbonate (2x200ml). The combined aqueous extracts are adjusted with aqueous hydrochloric acid (2M) to pH3 and extracted with ethyl acetate (3x200ml). The combined ethyl acetate fractions are dried (MgSO4) and the residue recrystallised (3x) from ethyl acetate/hexane to give 3,3-dimethyl-2,Sdioxo- 1,2,3,4-tetrahydro-quinolin-6-yl)-acetic acid ethyl ester as white crystals.

c) Aluminium chloride (2.819) is dissolved in dry ether (15ml) and lithium aluminium hydride (M in THF, 26.3ml) is added slowly at room temperature under nitrogen to maintain a gentle reflux. The mixture is stirred for 30 minutes. 3,3-Dimethyl-2,4 dioxo-1 ,2,3,4-tetrahydro-quinolin-6-yl)-acetic acid ethyl ester (2.99) is dissolved in dry THF (30ml) and added slowly to maintain a gentle reflux. The mixture is stirred at room temperature for 2 hours, water (68ml) and aqueous sodium hydroxide (M, 34ml) are added cautiously to quench the reaction mixture, ether (30ml) is added and the mixture is stirred at 20 C for 30 minutes. The ether is decanted and the reside is washed with more ether (2x30ml) and decanted. The combined ether phases are dried (MgS04) and evaporated to give a yellow oil which is preabsorbed on silicagel and purified by column chromatography using ethyl acetate:hexane (1:2, by vol.) as eluant to give 2-(3,3iimethyl-1 ,2,3,4-tetrahydro-quinolin-6-yl)-ethano as a beige solid.

d) 2-(3,3-Dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethanol (880mg), imidazole (642mg) and tert.-butyl-diphenyl-silyl chloride are dissolved in DMF (3ml) and stirred at 20'C for 70 hours. The mixture is diluted with ethyl acetate (1 Oml) and extracted with aqueous hydrchloric acid (0.1 M, 2x20ml). The extracts are back-extracted with ethyl acetate (1 Oml) and the combined ethyl acetate phases are dried (MgSO4). The solid product which precipitates out over the MgSO4 is filtered off. The filtrate is evaporated and the residue is purified by crystallising from ethyl acetate and column chromatography on silicagel using hexane/ethyl acetate (3:1, by vol.) as eluant to yield further St(2-tert.-butyl-diphenyl-silanyloxy)-ethyll-3w3-dimethy 1,2,3,4-tetrahydro- quinoline as a white solid.

e) 6-[(2-te rt.- Butyl-diphenyl-silanyloxy)-ethyl]-3 ,3-dimethyl-1 ,2,3 ,4-tetrahydro-quino{ine (813mg) and pyridine/sulfur trioxide complex (1.179) in toluene (10ml) is heated at reflux for 3 hours. The mixture is cooled and poured into ice/water (25ml). The solution is extracted with ethyl acetate (3x25ml) and the combined extracts are dried (MgS04) and evaporated. The residue is purified by column chromatography on silicagel using methanol:dichloromethane (1:9, by vol.) as eluant to give 6j(2-tert.- butyl-diphenyl-silanyloxy)-ethyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid as an off-white foam.

f) 6-[(2-tert.-Butyl-diphenyl-silanyloxy)-ethyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline8sulfonic acid (IOOmg) is dissolved in DMID (1 ml) and pyridine (40.1) and the solution is cooled to O'C under nitrogen. Phosphoryl chloride (40.1) is added and the mixture is stirred at 20'C for 30 minutes and poured into ethyl acetate (5ml). The solution is extracted with water (2x25ml), the water back-extracted with ethyl acetate (1 Oml) and the combined organic phases are dried (MgSO4) and evaporated to give 6-t(2-tert.- butyl-diphenyl-silanyloxy)-ethyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonyl chloride as a yellow oil which is held in vacuo (NaOH pellets) and is suitable for immediate use.

Reagent 15 a) 2,2-Dimethyl-N-(4-nitro-phenyl)-malonamic acid (35.69) is added in one charge to a stirring solution of phosphorus pentoxide (11.0g) in methane sulfonic acid (200ml) at 70'C.

The mixture is heated to 100 C and stirred for 16 hours. The reaction mixture is cooled and poured into iced water (1,500ml) and extracted with ethyl acetate (3x500ml). The combined extracts are washed with water (500ml), dried (MgS04) and evaporated to dryness. The residue is re-crystallised from ethyl acetate to give 3,3-dimethyl-6-nitro-1,2,3,4 tetrahydro quinolin-2,4-dione as beige crystals.

b) 3,3-Dimethyl-6-nitro-1,2,3,4 tetrahydro-quinolin-2,4-dione (23.79) is dissolved in a mixture of dioxan (250ml) and methanol (50ml) and the solution is hydrogenated (1 atm.) at 20'C in the presence of 10% palladium on charcoal (2.59) for 36 hours. The catalyst is removed by filtration and solvents are removed by rotary evaporation. The residue is dissolved in ethyl acetate (250ml) and extracted with aqueous hydrochloric acid (2M, 2x200ml). The combined extracts are neutralised with aqueous sodium hydroxide (2M) and extracted with ethyl acetate (3x150ml). The combined extracts are dried (MgSO4) and evaporated to give 6amino-3,3aimethyl-l ,2,3,4-tetrahydro-quinoiin-2,4-dione as an offwhite solid.

c) Amino-3,3 < limethyl-1 ,2,3,4-tetrahydro-quinolin-2,4-dione (149) in dry THF (100ml) is added slowly to a mixture of lithium aluminium hydride (M in THF, 171 ml) and aluminium trichloride (18.129) in dry ether (100ml) under an atmosphere of dry nitrogen. The mixture is stirred at 20 c for 4 hours, cooled to O'C and crushed ice (100ml) is added slowly.

Aqueous sodium hydroxide (M, 50ml) is added followed by ether (200ml). The mixture is stirred vigorously for 30 minutes and the ether decanted. Further portions (2x200ml) of ether are added, stirred and decanted as described. The combined ether extracts are dried (MgSO4) and solvent is removed by rotary evaporation. The residue is purified by column chromatography on silicagel using methanol:dichloromethane (1:9, by vol.) as eluant to give 6-amino-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline as an oil which is used immediately.

d) 6-Amino-3,3-dimethyl-1 ,2,3,4-tetrahydro-qu inoline (4.479) and tosyl chloride (4.83g) are dissolved in dichloromethane (100ml) at 0'C and triethylamine (3.54ml) is added. The mixture is stirred for 18 hours at 4 C and solvent is removed by rotary evaporation. The crude product is purified by column chromatography on silicagel using hexane:ethyl acetate (2:1, by vol.) as eluant to give N-(3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)4-meelyl- benzenesulfonamide as an off-white solid.

e) N-(3,3-Dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-4-methyl-benzene-sulfonamWe (4.1 g) and pyridine sulfur trioxide complex (7.66g) are dissolved in pyridine (1 00ml) and heated at reflux for 3 hours. The cooled mixture is poured into iced water (500ml) and the solution is washed with ether (200ml). The ether is back extracted with water (2x100mi). The aqueous phases are combined and evaporated to dryness in vacuo. The residue is redissolved in aqueous sodium hydroxide (M, 100ml) and extracted with ethyl acetate (2x100ml). The aqueous phase is neutralised with aqueous hydrochloric acid to pH6 and extracted with ethyl acetate (2x1 00ml). The extract is dried (MgSO4) and the solvent removed by rotary evaporation. The product is azeotroped with acetone to give 3,3 dimethyl-6-(toluene4-sulionyl-amino)-l ,2,3,4-tetrahydro-quinoline-8-su Ifonic acid as a white solid.

f) 3,3-Dimethyl-6-(toluene-4-sulfonylamino)-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid (100mg) is dissolved in a mixture of DMID (1 ml) and pyridine (0.05ml) and phosphoryl chloride (0.05ml) is added with cooling. The mixture is stirred at 20'C for 20 minutes. The mixture is diluted with ethyl acetate ether (1:1, by vol., 10ml) and washed with water (2x5ml). The organic phase is dried (MgSO4) and evaporated. The bright yellow residue of 3,3-dimethyl-6-(toluene-4-sulfonylamino)-1,2,3,4-tetrahydro-quinoline-8-sulfonyl chloride is suitable for immediate use.

Reagent 16 a) 6-Amino-3.3-dimethyl-1 ,2,3,4-tetrahydro-quinoline (4.64g) is dissolved in dichloromethane (100ml) and triethylamine (3.6ml) is added. The mixture is cooled to 0 C and benzyl chloroformate (3.76ml) is added slowly over 10 minutes with vigorous stirring.

The mixture is stirred at 4 C for 16 hours and solvents are removed by rotary evaporation.

The residue is purified by column chromatography on silicagel using hexane:ethyl acetate (52, by vol.) as eluant to give 6-benzyloxycarbonylamino-3,3-dimethyl-1,2,3,4-tetrahydro- quinoline as a colourless oil.

b) 6-Benzylcarbonylamino-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline (29) and pyridine sulfur trioxide complex (4.119) are dissolved in pyridine (50ml) and the mixture is heated at reflux for 4 hours. The reaction mixture is poured into iced water (200ml) and extracted with ether (3x100ml) and the combined ether extracts washed with water (2x100ml). The combined aqueous phases are evaporated to dryness and the residue is redissolved in aqueous sodium hydroxide (M, 200ml) and extracted with ethyl acetate (3x100ml). The solution is neutralised and extracted with ethyl acetate (3x100ml). The combined organic phases are dried (MgS04) and evaporated. The crude product is purified by column chromatography on silicagel using methanol:dichioromethane (1:4, by vol.) as eluant to give 6 benzyloxycarbony] amino-3,3-dimethyl-l ,2,3,4-tetrahydro-quinoline-8-sulfonic acid as a white solid.

c) 6-Benzyloxycarbonylamino-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid (130mg) is dissolved in a mixture of DMID (2ml) and pyridine (0.06ml), the solution is cooled to O C and phosphoryl chloride (0.07ml) is added. The mixture is stirred at 20'C for 40 minutes, diluted with ethyl acetate (20ml) and washed with water (2x10ml). The organic phase is dried (MgSO4) and evaporated to dryness to give 6-benzyloxycarbonylamino-3,3 dimethyl-l ,2,3,4-tetrahydroquinoline-8-sulfonyl chloride as a yellow oil which is suitable for immediate use.

INTERMEDIATES All Intermediates have 1 H- and 1 3C-NMR spectra consistent with the claimed structure.

Intermediate 1 a) 2(S)-Am ino-3-benzothiazol-2-yl- 1 -[4-(2-fluoro-ethyl)-piperidin-1 -yl]-propan- 1 -one dihydrobromide (6.7g) and Huenig Base (3.5ml) are dissolved in dichloromethane (60ml) and the solution is cooled to 50C. 3-(8-Chlorosulfonyl-3,3-dimethyl-1 ,2,3,4- tetrahydro-quinolin-6-yl)-propionic acid ethyl ester (7.29) dissolved in dichloromethane (60ml) is added gradually at 50C with the solution maintained above pH9. The mixture is stirred for 16 hours, allowing the temperature to rise to ambient The solution is washed with citric acid solution (2x75ml, 10% aqueous), water (2x75ml), brine (40ml) and dried (MgSO4). Evaportaion of the solvent gives 3** {1(S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxoethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester as a pale buff crispy foam.

b) 3-(8-(1 (S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1 -yl]-2-oxo- ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester (93mg) is dissolved in methanol (6ml) and aqueous sodium hydroxide (M, 2ml) is added. The mixture is stirred at 20'C for 18 hours and aqueous hydrochloric acid (2M, 1ml) is added. Ethyl acetate (20ml) is added, the organic phase is washed with water (10ml) and dried (MgSO4) and evaporated to give 3-(8-(1 (S)-berzothlazoi-2- ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl-sulfamoyl}-3,3-dimethyl 1 ,2,3,4-tetrahydtoquinolin-6-yl)-propioni acid as a white solid, m.p. 2240C. lM+ttl = 630.50. (Found: C, 58.95; H, 6.05:, N, 8.86; S, 10.10; F = 3.13. C31H39N4O5S2F requires C, 59.03; H, 6.23; N, 8,88; S, 10.17; F = 3.01%).

Intermediate 2 Analogously as described for Intermediate 1 but using 8-chlorosulfonyl-3,3-dimethyl- 1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester in place of 3-(8- chlorosulfonyl-3,3-dimethyl-1 ,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester is prepared 8-{1 (S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo- ethyl-sulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester. After purification by flash chromatography on a column of silicagel using dichloromethane:ether (20:1 then 9:1, by vol.) as eluant and evaporation of the solvent, it is obtained as a colourless foam of which a portion (100mg) is dissolved in methanol (2ml) and aqueous sodium hydroxide (M, 1.267ml) is added. The mixture is stirred for 80 hours at 20'C, evaporated and the residue dissolved in water (10ml).

The solution is extracted with ether (3x1 Oml), acidified to pH2 (M aqueous hydrochloric acid) and the solution is extracted with ethyl acetate (3x10ml). The combined organic extracts are dried (Mg5O4) and evaporated to give cream crystals.

The product is isolated by flash column chromatography on a column of silicagel using dichloromethane:methanol (96:4, by vol.) as eluant. Evaporation of appropriate fractions of the eluate affords 8-(2benzothiazol-2-yl- 1 (S)-[4(2-fluoro-ethyl)-piperidine 1-carbonyl]-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid as a white solid. [M+K = 603.6.

Intermediate 3 Analogously as described for Intermediate 1 but using 3-(8-chlorosulfonyl-3,3-diethyl- 1,2,3 ,4-tetrahydro-quinolin-6yl)-propionic acid ethyl ester in place of 3-(8chlorosulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester is prepared 3-(8-(1 (S)-benzothiazol-2-yl-methyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2- oxo-ethylsulfamoyl)-3 ,3-diethyl-1,2,3 ,4-tetrahydro-quinoiin-6-yl)-propionic acid as a white solid. [M+H]+ = 659.8.

Intermediate 4 Analogously as described for Intermediate 1 but using 8-chlorosulfonyl-3,3-diethyl 1 ,2,3,4tetrahydrn-quinoline-6-carboxylic acid ethyl ester in place of 3-(S chlorosulfo nyl-3,3-dimethyl-l 1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester is prepared 8-(2-be nzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]ethylsulfamoyl}-3,3-diethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid as a white solid. [M+H]+ = 631.4.

Intermediate 5 Analogously as described for Intermediate 1 but using 3-(8-chlorosulfonyl-3(RS)methyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester in place of 3-(8chlorosulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester is prepared 3-(8-(2-benzoth iazol-2-yl-l (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]ethylsulfamoyl}-3(RS)-methyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester which is saponified as described for Intermediate 1 to the corresponding acid.

The compound is extracted after acidification (aqueous HCI) of the saponification mixture with ethyl acetate, and after water washing of the extracted solution and drying (MgSO4) is recovered on evaporation of the solvent as a white foam. [M+H]+ = 617.2.

Intermediate 6 Analogously as described for Intermediate 5 but using 8chlorosulfonyl-3(RS).ethyl 1,2,3,4-tetrahydro-quinolin-6-yl-propionic add ethyl ester in place of 8-chlorosutfonyl- 3(RS)-methyl-1,2,3,4-tetrahydro-quinolin-6-yl-propionic acid ethyl ester is prepared 3 (8-{2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl} 3(RS)-ethyl-1,2,3,4tetrahydrosuinolin-6-yl)-propionic acid. The compound is extracted after acidification (aqueous HCI) of the saponification mixture with ethyl acetate, and after water washing of the extracted solution and drying (MgSO4) is recovered on evaporation of the solvent as a white foam. [M+H]+ = 631.2.

Intermediate 7 Analogously as described for Intermediate 5 but using 8-chlorosulfonyl-3(RS)-propyr 1,2,3,4-tetrahydro-quinolin-6-yl-propionic add ethyl ester in place of 8chlornsulfonyl- 3(RS)-methyl-1,2,3,4-tetrahydro-quinolin-6-yl-propionic acid ethyl ester is prepared 3 (8-{2-benzothlazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl} 3(RS)-propyl-1,2,3,stetrahydrosuinolin-6-yl)-propionic acid. The compound precipitates on acidification (aqueous HCI) of the saponification mixture and, after solution of the precipitate in ethyl acetate, water washing of the solution and drying is recovered on evaporation of the solvent as a white foam. [M+H]+ = 645.2.

Intermediate 8 Analogously as described for Intermediate 5 but using Schlorosulfonyl-3(RS)- isopropyl-l ,2,3,4-tetrahydroquinoiin-6-ylgropionic acid ethyl ester in place of S chlorosulfonyl-3(RS)-methyl-1,2,3,4-tetrahydro-quinolin-6-yl-propionic acid ethyl ester is prepared 3-(8-{2-benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl ethylsulfamoyl}-3(RS)-isopropyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid which is obtained as a white foam after isolation by chromatography on a column of silicagel which is eluted with dichloromethane:methanol (20:1, by vol.). [M+H)+ = 646.1.

Intermediate 9 Analogously as described for intermediate 5 but using 8chlornsulfonyl-3(RS)-isobutyl- 1,2,3,4-tetrahydro-quinolin-6-yl-propionic acid ethyl ester in place of 8-chlorosulfonyl 3(RS)-methyl-1,2,3,4-tetrahydro-quinolin-6-yl-prOpiOniC acid ethyl ester is prepared 3 (8-(2-benzothiazol-2-yl-l (S)-[4-(24luoro-ethyl)-piperidine- 1 -carbonyU-ethylsulfamoyl)- 3(RS)-isobutyl-l ,2,3 ,4-tetrahydroquinolin-6-yl)-propionic acid. The compound precipitates on acidification (aqueous HCI) of the saponification mixture and, after solution of the precipitate in ethyl acetate, water washing of the solution and drying (MgS04) is recovered on evaporation of the solvent as a white foam. [M+H]+ = 659.2.

Intermediate 10 Analogously as described for Intermediate 1 but using 3-(8-chlorosulfonyl-1 ,2,3,4tetrahydro-quinolin-6-yl)-propionic acid ethyl ester in place of 3-(8-chlorosulfonyl-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester is prepared 3-(8-(2- benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-1,2,3,4tetrahydro-quinolin-6-yl)-propionic acid which is obtained as a white foam. [M+H]+ = 603.2.

Intermediate 11 Analogously as described for Intermediate 5 but using 3-(8-chlorosulfonyl-3(RS)-ethoxy- 1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester in place of 3-(8-chlorosulfonyl 3(RS)-methyl-1,2,3 ,4-tetrahydroquinolin-6-yl)-propionic acid ethyl ester is prepared 3-(8 {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3(RS) ethoxy-1,2,3 ,4-tetrahydro-qu inolin-6-yl)-propionic acid. It is obtained as a white foam.

[M+H]+ = 647.4.

Intermediate 12 Analogously as described for Intermediate 1 but using 3-(8-chlorosulfonyl-3(RS) methoxymethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester in place of 3-(8-chlorosulfonyl-3,3-dimethyl-1 ,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester is prepared 3-(8-(2-benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-1- carbonyl]-ethylsulfamoyl}-3(RS)-methoxymethyl-1,2,3,4-tetrahydro-quinolin-6-yl)propionic acid which is obtained pure as a precipitated solid on acidification of the saponification mixture of the ethyl ester precursor. [M+H]+ = 647.4 Intermediate 13 a) Analogously as described for Intermediate 1 but using 6-[(2-tert.-butyl-diphenylsilanyloxy)-ethyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonyl chloride in place of 3-(8-chlorosulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid ethyl ester is prepared 6-[(2-tert.-butyl-diphenyl-silanyloxy)-ethyl]-3,3-dimethyl-1,2,3,4- tetrahydro-quinoline-8-sulfonic acid {1(S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl) piperidin-l -y-2-oxo-ethyl)-amide. It is purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (1:1, by vol.) as eluant.

b) 6-[(2-tert-Butyl-diphenyl-silanyloxy)-ethyl]-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-8-sulfonic acid {1(S)-benzo-thiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin 1-yl]-2-oxo-ethyl)-amide (245mg) dissolved in dry THF (10ml) and TBAF (1M in THF, 0.575ml) are mixed and stirred for 70 hours at 20'C. The solution is pre-absorbed onto silicagei and purified by column chromatography on a column of silicagel using ethyl acetate:hexane (2:1, by vol.) as eluant. 6-(2-Hydroxy-ethyl)-3,3-dimethyl- 1,2,3 ,4-tetrahydro-quinoline-8-sulfonic acid (1 (S)-benzothiazol-2-ylmethyl-2-[4-(2 fiuoro-ethyi)-piperidin-l -yl]-2-oxo-ethyl)-amide is obtained as a stable solid after freeze-drying. [M+H]+ = 603.

Intermediate 14 3-(8-(1 (S)-Benzothiazol-2-ylmethyl-2-f4-(2-f luorcFethyl)-piperidi n-l -yl]-2-oxo-ethyl-su Ifamoyl) 3,3-dimethyl-1 ,2,3,4.tetrahydro-quinolin-6-yl)-propanoic acid (500mg), diphenylphosphoryl azide (0.51 ml) and triethylamine (0.36ml) are dissolved in toluene (40ml) and heated at 100 C for 3 hours under an atmosphere of nitrogen. The mixture is cooled and concentrated.

Acetone (40ml), water (10ml) and concentrated sulfuric acid (29) are added in one portion with stirring and the mixture is stirred for 30 minutes at room temperature. The mixture is concentrated by removal of solvents, ethyl acetate (5Oml) is added and the solution is extracted with portions (3x20ml) of aqueous hydrochloric acid (2M). The combined aqueous extracts are washed with ethyl acetate (20ml), adjusted to alkaline pH with aqueous sodium hydroxide (4M) and extracted with portions (3x10ml) of dichloromethane. The combined extracts are washed with brine (2x25ml), dried (MgS04) and evaporated to give S(2-amino- ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2 fluoro-ethyl)-piperidine-1 -carbonylj-ethyl)-amide as an off-white foam which is sufficiently pure for further use. [M+H]+ = 602.3.

Intermediate 15 6-(2-Hydroxy-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {1(S)benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide (0.20g) and triethylamine (0.15ml) are dissolved in dichloromethane (10ml) , methanesulfonyl chloride (0.063ml) is added and the mixture is stirred at room temperature for 2 hours. The solution is washed with portions (10ml) of aqueous hydrochloric acid (M, 2x) and saturated aqueous sodium bicarbonate, dried (MgS04) and solvent removed by evaporation to give a yellow foam which is dissolved in ethyl acetate (10ml). A solution of methylamine (33% w/w in ethanol, 15ml) is added and the mixture is stirred at room temperature for 3 days. The solvents are evaporated to give a yellow solid which is purified by flash chromatography on silicagel using dichloromethane:methanol:acetic acid (45:5:1, by vol.) to give 3,3-dimethyl-6- (2-methylamino-ethyl)- 1,2,3 ,4-tetrahydro-quinoline-8-sulfonic acid (2-benzothiazol-2-yl-1 (S) [4-(2-fluoro-ethyl)-pipen'dine-i -carbonyl]-ethyl)-amide. [M+Hl+ = 616.7.

Intermediate 16 (2-Be nzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-Piperidine-l -carbonyl]-ethylsulfamoyl)-3 ,3- dimethyl-l ,2.3,4-tetrahydroquinoline-6-carboxylic acid (2.09) and triethylamine (0.52ml) are dissolved in DMF (50ml) and the solution is cooled to 0 C under an atmosphere of nitrogen.

Ethyl chloroformate (0.36ml) is added dropwise with stirring over 5 minutes and the solution is allowed to come to room temperature while stirring under nitrogen for a further 15 minutes.

Ether is added (100ml) and the mixture is washed with portions (4x50ml) of water and dried (MgSO4) and solvent removed by evaporation to give a yellow foam which is dissolved in ethanol (20ml) at cooled to OOC. Sodium borohydride (157mg) is added and the mixture stirred for 1 hour at OOC. Ether (100ml) is added and the solution is washed with saturated aqueous sodium bicarbonate solution (3x50ml), dried (MgSO4) and solvent removed by evaporation to give a yellow foam which is purified by flash chromatography on silicagel using ethyl acetate:hexane (5:2, by vol.) as eluant to give 6-hydroxymethyl-3,3-dimethyl-1,2,3,4- tetrahydroquinoline-8-sulfonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 carbonyl-ethyl)-amide as a white foam. [M+H]+ = 589.1.

Intermediate 17 Analogously as described for Intermediate 1 but starting from the analogous reagent to Reagent 1 synthesised by starting from 2(R)-benzyloxycarbonylamino-3-benzothiazol-2-yl- propionic acid benzyl ester is prepared 3-(8-(1 1(R)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-2-oxo-ethyl-sulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)propionic acid. 1M+H]+ = 631.3.

EXAMPLES All examples have 1H- and 13C-NMR spectra consistent with the claimed structure.

*Example 1 3-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl-sulfamoyl} 3,3 < limethyl-1 ,2,3 ,4-tetrahydro-quinolin-6-yl)-propion ic acid (300mg), diphenylphosphoryl azide (0.3ml) and triethylamine (0.216ml) are dissolved in toluene (24ml) and heated at 100'C for 2 hours under an atmosphere of nitrogen. The mixture is cooled and evaporated to dryness by rotary evaporation. The resulting oil is dissolved in dichloromethane (6ml) and methylamine (3ml, 33% w/v in ethanol) is added in one portion. The mixture is stirred at 20'C for 1 hour and the solvents removed by rotary evaporation. The residue is dissolved in dichloromethane (10ml) and washed with portions (2x10ml) of aqueous hydrochloric acid (2M), brine and saturated aqueous sodium bicarbonate solution, dried (MgSO4) and the solvents removed by rotary evaporation. The residue is purified by flash chromatography on a column of silicagel using methanol:dichloromethane (1:19, by vol.) as eluant to give 6[2-(3- methyl-ureido)-ethyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}-amide as a white foam. [M+H1+ = 659.6.

Similarly prepared by using the appropriate base is: Examole 2 6-[(2-Ureido)-ethyl]-3,3-dimethyl-1,2,3,4-tetra-hydro-quinoline-8-sulfonic acid {2-benzothiazol2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}-amide. [M+H]+ = 644.8.

Example 3 3-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl-sulfamoyl} 3,3-dimethyl-l ,2,3,4-tetrahydro-quinolin-6-yl)-propion acid (100mg) is dissolved in dry DMF (5ml), PyBOP (164mug) and Huenig Base (0.11ml) are added and the mixture is stirred at 20'C for 10 minutes. Methylamine hydrochloride (21mg) is added and the mixture stirred for 1 hour, diluted with ether (25ml) and the solution extracted with portions (3x20ml) of water.

The organic phase is dried (MgSO4) and the solvent is removed 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 3-(8-(1(S)-benzothiazol-2-ylmethyl.

2-[4-(2-fluoro-ethyl-piperidin-1-yl]-2-oxo-ethyl-sulfamoyl]-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-methyl-propionamide as a colourless oil. [M+H]+ = 644.6.

Similarly, by using the appropriate Intermediate and amine, a coupling agent (e.g. PyBOP, TBTU, TPTU), a base (e.g. Huenig Base, Triethylamine, NMM) and optionally an additive (e.g.

HOBt) in an appropriate solvent (e.g. dichloromethane, DMF) are prepared: Example 4 3-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl-sulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionamide. [M+H]+ = 630.8.

Example 5 3-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl-sulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N,N-dimethyl-propionamide as a colourless oil.

[M+H]+ = 657.8.

ExamDle 6 3,3-Dimethyl-6-(3-morpholin-4-yl-3-oxo-propyl)-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid (1 (S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide as a colourless oil. [M+H]+ = 699.9.

Example 7 By coupling of glycine ethyl ester and then saponification as described for Intermediate I b: 13- (8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionylamino]-acetic acid as a white solid. [M+H]+ = 688.7.

Example 8 3-(8-(2- Benzothiatol-2-yl-l (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethylsulfamoyI)-3 ,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-hydroxy-propionamide as a white foam. fM+H+ = 646.6.

Example 9 3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl-sulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-[2-(2-hydroxy-ethoxy)-ethyl]-propionamide as a white foam. lM+H]+ = 718.8.

Examole 10 4-[3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperazine-1-carboxylic acid tert.-butyl ester as a white foam. [M+H]+ = 800.0.

Examole 11 4-[3-(8-(2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperazine-1-carboxylic acid tert.-butyl ester (100mg) is dissolved in hydrogen chloride (saturated) in acetic acid (glacial) (1 ml) and the mixture is stirred at 20'C for 1 hour. Solvent is removed by rotary evaporation, the residue is dissolved in water (5ml) and the solution is adjusted to pH 10 with aqueous sodium hydroxide (2M). The solution is extracted with portions (3x10ml) of ethyl acetate. The combined extracts are dried (MgS04) and the solution evaporated. The residue is purified by flash chromatography on silicagel using dichloromethane:methanol (5:1, by vol.) as eluant to give 3.3aimethyl-6-(3-oxo-3-piperazin-l -yl-propyl)-1,2,3 ,4-tetrahydroquinoline-8-sulfon ic acid {1(S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide as a white foam. [M+H]+ = 699.7.

Example 12 3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-(2-morpholin-4-yl-ethyl)-propionamide. [M+H]+ = 743.7.

Example 13 2(S)-[3-(8-(2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionylamino]-3-hydroxypropionic acid methyl ester. [M+H]+ = 733.1.

Example 14 By saponification of Example 13: 2(S)-[3-(8-(2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)- piperidine-1-carbonyl]-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)propionylamino]-3-hydroxy-propionic acid. [M+H]+ = 718.9.

Example 15 6-[3-(4-Hydroxy-piperidin-1 -yl)-3-oxo-propyll-3 ,3-dimethyl-1 ,2,3,4-tetrahydroffluinolinvS sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}-amide.

[M+H]+ =715.1.

Example 16 1-[3-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxoethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine-4carboxylic acid methyl ester. [M+H]+ = 757.1.

Examole 17 By saponification of Example 16: 1-[3-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)propionyl]-piperidine-4-carboxylic acid. [M+H]+ = 742.7.

Example 18 {[3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-proplonyl]-methyl-amino}-acetic add ethyl ester.

[M+H]+ =730.6.

Example 19 By saponification of Example 18: ([3-(8-(2-Benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)piperidine-1-carbonyl]-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl) propionyl]-methyl-amino}-acetic acid. [M+H]+ = 702.6.

Examole 20 {4-[3-(8-{2-Benzothiazol-2-yl-1-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperazin-1-yl}-acetic acid ethyl ester.

[M+H]+ = 786.3.

Example 21 3-(8-(2-Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyli-ethylsulfamoyl)-3,3- dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-(2-hydroxy-ethyl)-propionamide. [M+H]+ = 674.1.

Example 22 3-(8-(2-lBenzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyl]-ethylsulfamoyl)-3,3- dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-(2-hydroxy-ethyl)-N-methyl-propionamide. [M+H]+ = 688.2.

Examole 23 By saponification of Example 20: (4-[3-(8-(2-Benzothiazol-2-yl-l (S)-[4-(2-fluoro-ethyl)piperidine- 1 -carbonyl]-ethylsulfamoyl)-3,3-dimethyl- ,2,3,4-tetrahydro-quinolin-6-yl)- propionyl]-piperazin-1 -yl)-acetic acid. [M+H]+ = 758.4.

Example 24 3,3-Dimethyl-6-(3-oxo-3-pyrrolidin-1-yl-propyl)-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {1(S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. [M+H]+ = 684.3.

Example 25 3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-[2-(3H-imidazol-4-yl)-ethyl]-propionamide.

[M+H]+ = 724.4.

Example 26 3,3-Dimethyl-6-[3-(4-methyl-pipe razin-1 -yl)-3-oxo-propyl]-1,2,3,4-tetrahydrosuinoline-8- sulfonic acid (2 -be nzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonylj-ethyl)-amide.

[M+H]+ = 713.2.

Example 27 6-(3-[4-(2-Hydroxy-ethyl)-piperazin-l -ylE3sxo-propyl)-3,3-dimethyl-1 ,2,3,4-tetrahydro- quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]ethyl)-amide. [M+Hl+ = 743.7.

Example 28 3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-(2-pyridin-4-yl-ethyl)-propionamide. [M+H]+ = 735.7.

Example 29 3,3-Dimethyl-6-[3-(4-morpholin-4-yl-piperidin-1-yl)-3-oxo-propyl]-1,2,3,4-tetrahydro-quinoline8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}amide. [M+H]+ = 783.7.

Examole 30 6-{3-[4-(2-Methoxy-ethylamino)-piperidin-1-yl]-3-oxo-propyl}-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-8-sulfonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]- ethyl)-amide. [M+H]+ = 771.4.

Example 31 3,3-Dimethyl-6-(3-oxo-3-thiomorpholin-4-yl-propyl)-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {1(S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl)-amide.

[M+H]+ = 717.7.

Example 32 3-(8-(2-Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyl]-ethylsulfamoyl)-3,3 dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-methyl-N-(2-morpholin-4-yl-ethyl)-propionamide.

[M+Hl+ = 757.3.

Example 33 Methanesulfonic acid 1 -[3-(8-(2- benzoth iazol-2 -yl - 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1- carbonyl]-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidin-4yl ester. [M+H-S02CH3]+ = 713.5.

Example 34 6-[3-(4-Acatyl-piperazin-1-yl)-3-oxo-propyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8sulfonic acid (1 (S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1 -yl]-2-oxo-ethyl}- amide. [M+H]+ = 741.4.

Examole 35 3,3-Dimethyl-6-(3-[4-(morpholine-4-carbonyl)-piperazin- 1 -yl]-3-oxo-propyl)- 1 ,2,3,4-tetrahydro- quinoline-8-sulfonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]- ethyl}-amide. [M+H]+ = 812.4.

Example 36 4[3-(8-(2- Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyl]-ethylsulfamoyl)-3 ,3- dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperazine-1-carboxylic acid dim

Example 37 3,3-Dimethyl-6-[3-oxo-3-(4-pyridin-4-ylmethyl-piperazin-1-yl)-propyl]-1,2,3,4-tetrahydroquinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]ethyl}-amide. [M+H]+ = 790.3.

Example 38 3,3-Dimethyl-6-[3-oxo-3-(4-pyridin-3-ylmethyl-piperazin-1-yl)-propyl]-1,2,3,4-tetrahydroquinoline-8-sulfonic acid (2benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -calbonyl]- ethyl)-amide. [M+K]+ = 790.2.

Example 39 3,3-Dimethyl-6-[3oxo-3-(4-pyridin-2-ylmethyl-piperazin-1 -yl)-propy0-1,2,3,Stetrahydro quinoline-8-sulfonic acid (2-benzothiazol-2-yl- I (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]- ethyl)-amide. [M+H]+ = 790.2.

Example 40 3,3-Dimethyl-6-{3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3-oxo-propyl}-1,2,3,4tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1carbonyl]-ethyl}-amide. [M+H]+ = 826.3. Crystallised from ethyl acetate, m.p. 1600C.

Examole 41 3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3 dimethyl-1 ,2,3 ,4-letrahydrn-quinolin-6-yl)-N-[2-(2-hydrnxy-ethoxy)-ethyl]-N-methyl- propionamide. [M+H]+ = 732.2.

Example 42 6-[3-(4-Methanesulfonyl-piperazin-1-yl)-3-oxo-propyl]-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl] ethyl)-amide. [M+H]+ = 777.3.

ExamDle 43 6[3-(4-Methanesu Ifonylamino-piperidin-l -yl)-3-oxo-propyl]-3 ,3-dimethyl-l ,2,3,4-tetrahydro- quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]ethyl)-arnide. [M+H]+ = 791.5.

Example 44 1-[3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-proplonyl]-pyrrolidine-2(S)-carboxylic acid methyl ester. [M+H]+ = 742.4.

Examole 45 By saponification of Example 44: 1-[3-(8-{1(S)-Benzothi ol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)propionyl]-pyrrolidine-2(S)-carboxylic acid. [M+H]+ = 728.4.

Example 46 3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-morpholin-4-yl-propionamide. [M+H]+ = 715.3.

Example 47 1-[3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine-3(RS)-carboxylic acid ethyl ester. [M+H]+ = 770.3.

Example 48 By saponification of Example 47: 1 -[3-(8-(2-Be nzothiazol-2-yl-l (S)-[4-(2-fluoro-ethyl)- piperidine-1-carbonyl]-ethylsuofamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)propionyl]-piperidine-3(RS)-carboxylic acid. [M+H]+ = 742.3.

Examole 49 3,3-Dimethyl-6-[3-oxo-3-(3-oxo-piperazin-1-yl)-propyl]-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonylethyI)-arnide.

[M+H]+ = 713.4.

Example 50 6-[3-(4-Methoxymethoxy-piperidin-1-yl)-3-oxo-propyl]-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-8-sulfonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluorn-ethyl)-piperidine-1 -carbonyl]- ethyl}-amide. [M+H]+ = 758.6.

Example 51 3-[3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsuofamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionylamino]-2,2-dimethyl-proplonic acid.

ethyl ester. [M+HJ+ = 758.6.

Example 52 3-[3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionylamino]-2,2-dimethyl-propionic acid.

[M+H]+ = 730.5.

Example 53 6-[3-(4-Formyl-piperazin-1-yl)-3-oxo-propyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8sulfonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethyl-amide.

[M+H]+ = 727.3.

Example 54 3,3-Dimethyl-6-(3-oxo-3-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-propyl}-1,2,3,4 tetrahydro-quinoline-8-sulfonic acid (2benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-l - carbonyl]-ethyl)-amide. [M+H]+ = 810.3.

Example 55 6-(3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-3-oxo-propyl)-3,3-dimethyl-1,2,3,4tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 carbonyl]-ethyl)-amide. [M+H]+ = 787.3.

Example 56 2-(4-[3-(8(2-Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyq-ethylsulfamoyl}- 3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperazin-1-yl}-N,N-dimethylacetamide. [M+H]+ = 785.3.

Examole 57 3-[3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl} 3,3-dimethyl-1,2,3 ,4-tetrahydroquinoli n-6-yl )-propionylamino]-2 ,2-dimethyl-propionamide .

[M+H]+ = 729.6.

Examole 58 3,3-Dimethyl-6-{3-[4-(morpholine-4-carbonyl)-piperidin-1-yl]-3-oxo-propyl}-1,2,3,4-tetrahydroquinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl] ethyl)-amide. [M+H]+ = 811.4.

Examole 59 Example 17 is further derivatised by the same coupling procedure with the appropriate base to give: 1 -[3-(8-(2-Benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-l -carbonyl] ethyisulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine-4carboxylic acid dimethylamide. [M+H]+ = 769.0.

Example 60 6-{3-[2(RS)-(2-Hydroxy-ethyl)-piperidin-1-yl]-3-oxo-propyl}-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl} ethyI)-amide. [M+H]+ = 742.2.

Example 61 Example 17 is further derivatised by the same coupling procedure with the appropriate base to give: 3,3-Dimethyl-6-(3-{4-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]piperidin-1-yl}-3-oxo-propyl)-1,2,3,4-tetrahydro-quinoline-8-sulfonic aicd {2-benzothiazol-2 yl-I l-1(S)-[4-(2-fluoro-ethyl)-piperidine-1 -catbony-ethyi)-amide. [M+H]+ = 937.4 Example 62 Example 45 is further derivatised by the same coupling procedure with the appropriate base to give: 3,3-Dimethyl-6-{3-[2(S)-(morpholine-4-carbonyl)-pyrrolidin-1-yl]-3-oxo-propyl}-1,2,3,4 tetrahydrnquinoline-8-sulfonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1- carbonyl]-ethyl)-amide. [M+H]+ = 797.5.

Example 63 Example 45 is further derivatised by the same coupling procedure with the appropriate base to give: 6-{3-[2(S)-(4-Formyl-piperazine-1-carbonyl)-pyrrolidin-1-yl]-3-oxo-propyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoroethyl)-piperidine-1 -carbonyl]-ethyl)-amide. [M+H]+ = 824.8.

Examole 64 By coupling with the appropriate alcohol using DMAP and DCC in the presence of HOBt, similarly is prepared 3-(8-{2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]- ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid 2-morpholin-4yl-ethyl ester. [M+H]+ = 744.3.

Example 65 Example 45 is further derivatised by the same coupling procedure with the appropriate base to give: 1 -[3-(8-(2-Benzothiazol-2-yl-1 (S)-[4(2-fluoro-ethyl)-piperidine-1 -carbonyl]- ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-pyrrolidine-2(S)carboxylic acid dimethylamide. [M+H]+ = 755.4.

Example 66 3,3-Dimethyl-6-{3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin- 1 -yl]-3-oxo-propyl)- 1,2,3,4- tetrahydro-quinoline-8-sulfonic acid (2-benzothiazol-2-yl- 1 (R)-[4-(2-fluoro-ethyl)siperidine-1 carbonyl]-ethyl)-amide. [M+H]+ = 826.6.

Examole 67 3-[(8-(1 (S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl) -piperidin-1 -yl]-2-oxo-ethylsulfamoyl)- 3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amino]-acetic acid ethyl ester.

Example 68 By saponifcation of Example 67: 3-[(8-((1 S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)piperidin-1-yl]-2-oxo-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)amino]-acetic acid, isolated as the sodium salt. FAB-MS [M+Na]+ = 682.5.

Examole 69 3-[(8-(1 (S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1 -yl]-2-oxo-ethylsulfamoyl)- 3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amino]-propionic acid ethyl ester.

Example 70 By saponifcation of Example 69: 3-[(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)- piperidin-1-yl]-2-oxo-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)amino]-propionic acid, isolated both as the sodium salt and as the free acid.

Example 71 3-[(8-( 1 (S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1 -yl]-2-oxo-ethylsulfamoyl)- 3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amino]-acetic acid (2-morpholin-4-ylethyl)-amide.

Example 72 2(S)-[(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxoethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amino]-3-hydroxypropionic acid ethyl ester.

Examole 73 By saponification of Example 72: 2(S)1(8-{1 (S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-2-oxo-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6carbonyl)-amino]-3-hydroxy-propionic acid, isolated as the sodium salt.

Example 74 [(8-( 1 (S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1 -yl]-2-oxo-ethylsulfamoyl)- 3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-methyl amino]-acetic acid ethyl ester.

Example 75 8(2-Benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyl]-ethylsulfamoy1)-3,3- dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide.

Example 76 3,3-Diethyl-6-(3-morpholin-4-yl-3-oxo-propyl)-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2 benzoth iazol-2-yl-l (S)-[4-(2-fl uoro-ethyl)-piperidine- 1 -carbonyl]-ethyl)-amide. [M+H]+ = 728.7.

Example 77 3-(8-(2-Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyl]-ethylsulfamoyl)-3,3- diethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N ,N-dimethyl-propionamide . [M+H]+ = 686.6.

Examole 78 4-[3-(8-(2-Benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl3-ethylsulfamoyll- 3,3-diethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperazine-1-acetic acid, after saponification of the methyl ester precursor and isolation as the hydrochloride salt. [M+H]+ = 785.5.

Example 79 1 -[3-(8-(2-Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethylsulfamoyl)3,3-diethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-aziridine-2(S)-carboxylic acid, after saponification of the methyl ester precursor. [M+H]+ = 727.1 (minor), [M+H-COOH]+ = 681.7 (major).

Example 80 3-(8-(2-Benzothiazo I-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyl]-ethylsulfamoyl)-3,3- diethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N,N-bis-(2-hydroxy-ethyl)-propionamide. [M+H]+ = 746.8.

Example 81 3,3-Diethyl-6-(3-oxo-3-piperazin-1-yl-propyl)-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}-amide isolated, after acidolysis of the tert.-butoxycarbonyl presursor, as the hydrochloride salt. [M+H]+ =728.1 Example 82 1-[3-(8-(2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3,3-diethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine-4-carboxylic acid, after saponification of the methyl ester precursor. [M+H]+ = 771.6.

Example 83 3,3-Diethyl-6-{3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3-oxo-propyl}-1,2,3,4tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1 carbonyl]-ethyl)-amide. [M+H]+ = 854.5.

Example 84 2(S)-[((2-Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyll-ethylsuifamoyl}- 3,3-diethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amino]-3-hydroxy-propionic acid. MS (Cl, methane) lM+CH5-H20]+ =717.

Example 85 3,3-Diethyl-6-(morpholine-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}-amide. [M+H]+ = 700.5.

Example 86 8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3diethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide.

[M+H]+ = 718.6.

Examole 87 8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3diethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.

[M+H]+ = 743.5.

Example 88 8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3diethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-methylamide. [M+H]+ = 732.3.

Example 89 3(RS)-Methyl-6-{3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3-oxo-propyl}-1,2,3,4 tetrahydrosuinoline-8-sulfonic acid (2-benzothiazol-2-yI- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1- carbonyl]-ethyl)-amide. [M+H]+ = 812.4.

Examole 90 1-[3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3(RS)-methyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine-4-carboxylic acid, after saponification of the methyl ester precursor. [M+H]+ = 728.5.

Examole 91 1 -[3-(8-(2-Benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethylsulfamoyl)- 3(RS)-ethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine-4-carboxylic acid, after saponification of the methyl ester precursor. [M+H]+ = 742.5.

Examole 92 3(RS)-Ethyl-6-{3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3-oxo-propyl}-1,2,3,4,tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1 carbonyl]-ethyl)-amide. [M+H]+ =826.5.

Example 93 3(RS)-Ethyl-6-{3-oxo-3-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-propyl}-1,2,3,4tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1carbonyl]-ethyl}-amide. [M+H]+ = 810.5.

Example 94 6-(3-Morpholin-4-yl-3-oxo-propyl)-3-propyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {1(S)benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. [M+H]+ = 714.4.

Examole 95 6-{3-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3-oxo-propyl}-3(RS)-propyl-1,2,3,4 tetrahydroquinoiine-8-su Ifonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-pip'eridine- 1- carbonyl]-ethyl}-amide. [M+H]+ = 840.4.

Example 96 1 -[3-(8-{1 (S)-Benzothiazol-2-ylmethyl-2-[4-(2-fi uo ro-ethyl)-piperidin-1 -yl]-2oxo- ethylsulfamoyl}-3-propyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine-4-carboxylic acid, after saponification of the methyl ester precursor. [M+H]+ = 756.5.

Example 97 3(RS)-isopropyl-6-{3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3-oxo-propyl}-1,2,3,4 tetrahydrosuinoline-8-sulfonic acid (2-benzothiazol-2-yI- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 - carbonyl]-ethyl)-amide. [M+H]+ = 840.5.

Examole 98 1 -[3-(8-(2-Benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethylsulfamoyl}- 3(RS)-isopropyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine-4-carboxylic acid, after saponification of the methyl ester precursor. [M+H]+ = 756.4.

Examole 99 3(RS)-isobutyl-6-{3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl}-3-oxo-propyl}-1,2,3,4 tetrahydroquinoline-8-sulfonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 carbonyl]-ethyl}-amide. [M+H]+ = 854.5.

Example 100 1-[3-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carboxyl]-ethylsulfamoyl}3(RS)-isobutyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine-4-carboxylic acid, after saponification of the methyl ester precursor. [M+H]+ = 770.7.

Example 101 6-(3-[4-(2-Morph olin 4-yl -2-oxo-ethyl)-piperazin- 1 -yl]-3-oxo-propyi)- 1 ,2,3,4-tetrahydro- quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl] ethyl)-amide. [M+H]+ = 798.4.

Example 102 3(RS)-Ethoxy-6-{3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3-oxo-propyl}-1,2,3,4tetrahydro-quinoline-8-sulfonic acid (2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 carbonyl]-ethyl}-amide. [M+H]+ = 842.7 Example 103 3-(8-(2-Benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyll-ethylsulfarnoyl}- 3(RS)-methoxymethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N,N-dimethyl-propionamide. [M+H]+ = 674.6.

Example 104 3(RS)-Methoxymethyl-6-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1,2,3,4-tetrahydroquinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]ethyl)-amide. [M+H]+ = 729.5.

Example 105 3(RS)-Methoxymethyl-6-{3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3-oxo-propyl}1 ,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)- piperidine-1 -carbonyl]-ethyl}-amide. [M+H]+ = 842.4.

Example 106 1-[3-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxoethylsulfamoyl)-3(RS)-methoxymethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionyl]-piperidine4-carboxylic acid, after saponification of the methyl ester precursor. [M+H]+ = 758.5.

Examole 107 3-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo-ethyl-sulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid (250mg) is dissolved in dry THF (5ml) and thionyl chloride (0.034ml) is added. The mixture is stirred at 80 C for 3 hours and cooled to 20'C. 5-Aminotetrazole (147mg) is added with sufficient dry DMF to ensure solution and the mixture is stirred at 20'C for 16 hours, diluted with ethyl acetate (25ml) and washed with portions (10ml) of aqueous citric acid solution (10% w/v), water, saturated aqueous sodium bicarbonate solution, dried (MgSO4) and the solvents removed by rotary evaporation.

The residue is purified on a column of silicagel using ethyl acetate:hexane (1:1, by vol.) as eluant to give 3-(8-{1 (S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1 -y0-2-oxo- ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-N-(1H-tetrazol-5-yl)propionamide as a pale yellow oil. [M+Na]+ = 721.4 Example 108 6-Hydroxymethyl-3 ,3-dimethyl- 1 ,2,3 ,4-tetrahydroguinolin e-8sulf onic acid (2-benzoth iazol-2- yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonylj-ethyl)-amide (115mg), methyl isocyanate (0.11ml) and acetic acid (5z1) are dissolved in dichloromethane (6ml) and the solution is heated at 50 C for 24 hours in a sealed tube. After cooling, ether (20ml) is added and the mixture is washed with saturated aqueous sodium bicarbonate (2x20ml), dried (MgS04) and the solvent evaporated to give methyl-carbamic acid 8-{2-benzothiazol-2-yl-1(S)-[4-(2-fluoro- ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6ylmethyl ester as a white foam which is purified by flash chromatography on silicagel using ethyl acetate:hexane (7:3, by vol.) as eluant. [M+H]+ = 646.4.

Similarly prepared by using the appropriate Intermediate is: Examole 109 6-(2-Methylcarbamoyloxy-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid ((1 S)-benzothiazol-2-ylmethyl-2-[4-fluoro-ethyl-piperidin-1-yl]-2-oxo-ethyl}-amide. [M+H]+ - 659.8.

ExamDle 110 By reaction of Reagents 1 and 15: 3,3-Dimethyl-6-(toluene-4-sulfonylamino)-1,2,3,4- tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1 carbonyl]-ethyl)-amide. [M+H]+ = 727.4.

Example 111 By reaction of Reagents 1 and 16: (8-(2-Benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)piperidine-1-carbonyl]-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)carbamic acid benzyl ester. [M+H]+ = 708.

Example 112 6-(2-Hydroxy-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {1(S)benzothiazol-2-ylmethyl-2-[4-fluoro-ethyl-piperidin-1-yl]-2-oxo-ethyl}-amide (100mg) and Huenig Base (0.50mi) are dissolved in DMF (2ml) and cooled to 0 C. Methanesulfonyl chloride (0.013ml) is added with stirring and the stirred mixture is kept for 30 minutes at O'C.

Imidazole (34mg) is added and the mixture is heated at reflux for 24 hours with stirring. The mixture is cooled and diluted with ethyl acetate (20ml), washed with water (2x10ml), the organic phase dried (MgS04) and evaporated by rotary evaporation. The residue is purified by flash chromatography on a column of silicagel using dichloromethane: methanol 30:1, by vol.) as eluant to give 6-(2-imidazol-1-yl-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8- sulfonic acid (2-benzothiazol-2-yl-I (S)-(4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethyl{-amide as a yellow oil. [M+Hl+ = 653.8.

Similarly prepared by using the appropriate base are: Example 113 6-(2-Azido-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2 yl-1(S)-1s(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}-amide. (M+H]+ = 628.5.

Example 114 3,3-Dimethyl-6-(2-morpholin-4-yl-ethyl)-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2benzothiazol-2-yl-1 (S)-[4-(2-iluoro-ethyl)-piperidine-l -carbonyl]-ethyl}-amide. lM+Hls = 672.8.

Example 115 3,3-Dimethyl-6-(toiuene-4-sulfonylamino)-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}-amide (171mg) is dissolved in hydrogen bromide in acetic acid (48% w/v, Sml) and the mixture is stirred at room temperature for 2.5 hours. The solvent is removed in vacuo and the residue purified by flash chromatography on silicagel using dichloromethane:methanol (30:1 then 20;1, by vol.) as eulant to give 6-amino-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid (2 benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}-amide hydrobromide.

[M+H]+ = 575.

Example 116 6-(2-Amino-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethyl)-amide (42mg) and Huenig Base (0.031ml) are dissolved in dichloromethane (3ml) and methyl chloroformate (0.006ml) is added. The minutes is stirred for 2 hours, ethyl acetate (1 Oml) is added and the solution is extracted with portions (1 Oml) of aqueous hydrochloric acid (2M saturated with NaCI), brine (2x), dried (MgS04) and solvents removed by evaporation. The residue is purified by flash chromatography on a column of silicagel using methanol:dichloromethane (1:24, by vol.) as eluant to give 6-(2-methoxycarbonyl-amino-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline- 8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}amide as a white foam. [M+H]+ = 660.8.

Similarly prepared by use of the appropriate Intermediate and acylating agent are: Example 117 Morpholine4-carboxylic acid [2-(8-(2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1- carbonyl]-ethylsulfamoyl)-3,3-dimethyl-1 ,2,3 ,4-tetrahydro-quinolin-6yl)-ethyl-amide.

[M+H]+ = 715.9.

Example 118 6-[2-(3,3-Dimethyl-ureido)-ethyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethyl)-amide. [M+H]+ = 674.3.

ExamDle 119 6-(2-Methanesulfonylamino-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid (1 (S)-benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-PiPeridin- 1 -yI]-2-oxo-ethyl)-amide.

[M+H]+ = 680.2.

Example 120 N-[2-(8-{2-Benzothlazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-acetamide. [M+H]+ = 644.6.

Example 121 N-[2-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxoethylsulfamoyl}-3,3-demethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-N-methyl-acetamide.

[M+H]+ = 658.8.

Example 122 Morpholine-4-carboxylic acid [2-(8-{2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1carbonyl]-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-methyl-amide.

[M+H]+ = 729.6.

Example 123 6-(2-Amino-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethyl}-amide (70mg) is dissolved in dichloromethane (1ml) and ethyl isocyanate (0.012ml) is added. The mixture is stifled for 15 minutes at room temperature, dichloromethane (5ml) is added and the solution is washed with portions (5ml) of aqueous hydrochloric acid (2M, 2x) and brine, dried (MgSO4) and solvent removed by rotary evaporation to give 6-[2-(3-ethyl-ureido)-ethyl]-3,3-dimethy ,2,3,4- tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1 carbonyli-ethyI)-amide obtained as a white powder after lyophilisation from water. [M+H]+ = 674.2.

Similarly prepared is Example 124 3-{3-[2-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-ureido}-propionic acid after saponification of the ethyl ester precursor. [M+H]+ = 717.6.

Example 125 6-(2-Amino-ethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid {2-benzothiazol-2 yl-I (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyll-ethyl)-amide (125mg) and Huenig Base (0.3ml) are dissolved in dichloromethane (10ml) and phosgene solution (1.93M in toluene, 0.1 8-{2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylcarbamoyl]-ethyl}-carbamic acid t-butyl ester as a white solid. The crude compound is purified by flash chromatography on a column of silicagel using ethyl acetate as eluant.

b) {2-[2-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylcarbamoyl]-ethyl}-carbamic acid tert.-butyl ester (54mg) is dissolved in hydrogen chloride in acetic acid (M, 0.5ml) and the mixture is stirred at 20'C for 15 minutes. The solution is dried by rotary evaporation and the residue triturated with ethyl acetate to give pure 3-amino-N-[2-(8-{2-benzothiazol-2-yl-1(S)-[4-(2-fluoro- ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)ethyl]-propionamide hydrochloride. [M+H]+ = 711.7.

Similarly prepared, from the appropriate Intermediate base, appropriate acid, a coupling agent (e.g. PyBOP, TBTU, TPTU), a base (e.g. Huenig Base, Triethylamine, NMM) and optionally an additive (e.g. HOBt) in an appropriate solvent (e.g. dichloromethane, DMF) and using saponification or acidolytic deprotection where required from a relevant generated precursor, are: Example 128 N-[2-(8-{2-Benzothlazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-succinamic acid. [M+H]+ = 703.1.

Example 129 N-[2-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl} 3,3-dimethyl- 1 ,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-3-methoxy-propionamide. [M+H]+ = 688.6.

Example 130 N-[2-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxoethylsulfamoyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-3-morpholin-4-ylpropionamide. [M+H]+ = 743.1.

Examole 131 4-Amino-N-[2-(8-{2-benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl] ethylsulfamoyI)-3,3-dimethyl- 1 ,2,3,4-tetrahydro-quinolin-6y1)-ethyl)-butyramide, isolated as the hydrochloride salt. [M+H]+ = 687.8.

Example 132 N-[2-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxo ethylsulfamoyl)-3,3 < limethyl-1 ,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-3-piperidin-1 -ylpropionamide. [M+H]+ = 741.8.

Examole 133 N-[2-(8(2-Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethylsulfamoyl)- 3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-2-hydroxy-acetamide. [M+H]+ = 660.7.

Example 134 N-[2-(8-(2-Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyl]-ethylsulfamoyl)- 3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-3-dimethylamino-propionamide. [M+H]+ = 701.9.

Examole 135 3-Amino-N-[2-(8(2-benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyl]ethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-N-methyl-propionamide, isolated as the hydrochloride salt. [M+H]+ = 687.5.

Examole 136 N-[2-(8-(2-Benzothiazol-2-yl- 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-ethylsulfamoyl)3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-N-methyl-succinamic acid. [M+H]+ = 716.2.

Example 137 N-12-(S{2-Benzothiazol-2-yl-1 (S)-[4-(2-fluoro-ethyl)-piperidine- 1 -carbonyQ-ethylsulfamoyl}- 3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-3-methoxy-N-emthyl-propionamide.

[M+H]+ =702.3.

Examole 138 N-[2-(8-{1(S)-Benzothiazol-2-ylmethyl-2-[4-(2-fluoro-ethyl)-piperidin-1-yl]-2-oxoethylsulfamoyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-N-methyl-2-morpholin-4yl-acetamide. [M+H]+ = 743.8 Example 139 N-[2-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-2-hydroxy-N-methyl-acetamide. [M+H]+ = 674.9.

Example 140 N-[2-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-N-methyl-3-morpholin-4-ylpropionamide. [M+H]+ = 757.9.

Example 141 N-[2-(8-{2-Benzothiazol-2-yl-1(S)-[4-(2-fluoro-ethyl)-piperidine-1-carbonyl]-ethylsulfamoyl}-3,3dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-N-methyl-succinamide. [M+H]+ = 716.7.

Examole 142 Determination of the potency of the compounds.

Ki value: The compounds are analysed for their effect on the human a-thrombin-catalysed hydrolysis of the substrate Kabi S-2238 (Kabi Vitrum (UK) Ltd). The Km and Kp values are derived from a Lineweaver-Burk plot of data, from which is calculated the Ki value for the inhibitors. The potency of compounds with respect to human athrombin is expressed as their kinetic inhibition constant (Ki).

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 3.125 M to l00M. 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 vehicle (water, methanol or DMSO) to give a final concentration close to the expected Ki, and into the second series is added an equivalent volume of the vehicle alone. The reactions are started by the addition of human a-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 absorbance 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 vehicle alone to give a range of concentrations from 0 to approximately 150 CLAM. 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 (500 is activated by incubating for 5 minutes at 370C with bovine cephalin reagent (Instrumentation Laboratory (UK) Ltd, APTT (Ellagic Acid) Test Kit, 50LJ), before initiating coagulation by the addition of caicium chloride solution (20mM, 50,us). 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 (Ki and APTT) against human thrombin

Ex Ki APTT Ex Ki APTT (nM) ( M) (nM) ( M) 7 86 6.6 65 30 5.8 9 48 8.0 78 18 4.2 11 24 5.5 82 34 5.2 12 40 6.7 83 70 4.0 14 52 6.8 89 55 4.3 17 733.69137 4.7 23 67 3.1 92 28 3.1 27 44 4.0 93 26 3.0 29 27 4.3 95 25 3.3 30 32 7.5 97 29 4.5 35 32 5.7 98 22 3.9 40 41 4.0 102 92 5.1 43 44 5.6 105 84 3.2 45 55 4.1 124 67 ~ 6.0 48 606.9 126 34 6.9 49 78 5.9 127 32 5.7 53 50 6.0 130 35 6.3 54 38 4.0 131 32 4.4 55 43 5.6 132 26 4.5 58 48 4.7 133 55 5.3 59 43 5.5 135 44 7.0 61 71 4.3 136 71 4.7 62 39 6.5 140 32 4.0 63 30 3.5 Using active substances as described in any of the foregoing Examples, the following dosage forms are made.

Example 143 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 Corn starch 35 Talcum 20 Magnesium stearate 5 Total 450 mg Example 144 Capsules for oral administration Capsules of the below were 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 Examole 145 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 (12)

1. Claims 1. A compound of the general formula I

   in which A and B are hydrogen, a C1-C5 alkyl which may be interrupted by one or more oxygen atoms, C1 -C5 alkenyl, alkoxyalkyl, hydroxyalkyl, alkylthioalkyl, alkylamino, dialkylamino or trialkylamino, or together form a methylene group, or together with the carbon atom to which they are attached form a C3-C7 carbocylic ring; and C is a group -R-X in which R is a C1-C4 alkylene group optionally interrupted by oxygen or is a direct bond and X is an aminocarbonyl, carbonylamino, sulfonylamino, amino, azido or heterocyclic alkyl, or a salt thereof.
2. 2. A compound as claimed in claim 1 in which X is an aminocarbonyl group having the formula -CONR'R2 in which R1 is hydrogen, C1-C4 alkyl, or C1-C4 hydroxyalkyl wherein the alkyl groups are optionally interrupted by oxygen, R2 is hydrogen, C14 alkyl, hydroxy, C1 -C4 hydroxyalkyl optionally interrupted by oxygen, or (CqH2q)-Q where q is 1 to 4 and Q is COOR4 where R4 is hydrogen, C,-C4 alkyl or CONH2 and CqH is optionally substituted by hydroxy or interrupted by oxygen, or R2 is an optionally substituted 5 or 6 membered heterocyclic ring or heterocyclic alkyl group, or R' and R2 together with the nitrogen atom to which they are bound form an optionally substituted 5 or 6 membered heterocyclic ring.
3. 3. A compound as claimed in claim 1 in which X is a carbonylamino group having the formula -NR'CoR3 in which R' is as defined above and R3 is C1-C4 alkyl optionally interrupted by oxygen, C1-C4 alkoxy, CrClo aralkoxy, C1 -C4 hydroxyalkyl, C2-C5 carboxyalkyl, C2-Cs amidoalkyl, a 5 or 6 membered heterocyclic ring, or NRSRB where R5 and Re are hydrogen, C1-C4 alkyl, C1-C4 aminoalkyl, C2-Cs carboxyalkyl, C1-C4 hydroxyalkyl or a 5 or 6 membered heterocyclic ring.
4. 4. A compound as claimed in any preceding claim in which X is a C1-C4 alkyl-, aryl-, or heterocyclicalkyl- sulfonylamino group.
5. 5. A compound as claimed in any preceding claim in which X contains a heterocyclic group which is a pyrrolidyl, piperidyl, piperazinyl, morpholyl or thiazolyl group.
6. 6. A compound as claimed in any preceding claim in which X contains a heterocyclic group which is substituted by alkyl, hydroxy, carboxy, hydroxyalkyl, carboxyalkyl, alkylcarboxy, alkylcarboxyalkyl or an aminocarbonyl group, as defined in claim 2.
7. 7. A compound as claimed in any one of the preceding claims in which A and B are hydrogen or methyl.
8. 8. A compound as claimed in any preceding claim in which R is a -C2H4- group.
9. 9. A process for preparing a compound of formula I as defined in claim 1 which comprises reacting an aminoacyl amide of formula V H Aa base (V) with an arylsulfonic acid derivative of formula VI ArSO2 W (Vl) in which ArSO2 is

   in which C' is C or a precursor of C, Aa is

   and base is

   and, if necessary converting a precursor of C into C by reaction with a base or acylating agent.
10. 10. A process for preparing a compound of formula I as defined in claim 1 which comprises reacting an arylsulfonyl amino acid compound of formula Vll ArSO2Aa OH where ArSO2 and Aa are as defined in claim 9 with the base of formula IV as defined in claim 9 and, if necessary converting a precursor of C into C by reaction with a base or acylating agent
11. 11. A compound of formula VIII

    in which A, B and C are as defined in claim 1.
12. 12. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 together with a pharmaceutically acceptable carrier or diluent.