CA2260190A1 - New amidino derivatives and their use as thrombin inhibitors - Google Patents

Abstract

There are provided compounds of formula (I), wherein R1, R2, R3, Y, n and B
have meanings given in the description which are useful as competitive inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (e.g.
thrombosis) or as anticoagulants.

Description

CA 02260l90 l998-l2-29 NEW AMIDINO DERIVATIVES AND 1~1~;1~ USE AS THROMBIN
INHIBITORS

Field of the Invention This invention relates to novel ph~ ceutically useful compounds, in particular competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicaments, ph~ ceutical compositions Cont~ining them and synthetic routes to their production.

Background Blood coagulation is the key process involved in both haemostasis (i.e. the prevention of blood loss from a damaged vessel) and thrombosis (i.e. the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction).

Coagulation is the result of a complex series of enzymatic reactions. One of the ultimate steps in this series of reactions is the conversion of the 20 proenzyme prothrombin to the active enzyme thrombin.

Thrombin is known to play a central role in coagulation. It activates platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which polymerise spontaneously into fibrin polymers, and 25 activates factor XIII, which in turn crosslinks the polymers to form insoluble - fibrin. Furthermore, thrombin activates factor V and factor VIII leading to a "positive feedback" generation of thrombin from prothrombin.

By inhibiting the aggregation of platelets and the formation and crosslinking 30 of fibrin, effective inhibitors of thrombin would therefore be expected to exhibit antithrombotic activity. In addition, antithrombotic activity would be expected to be enhanced by effective inhibition of the positive feedback mech~ni.sm .

Prior Art The early development of low molecular weight inhibitors of thrombin has been described by Claesson in Blood Coagul. Fibrinol. (1994) 5, 411.

o Blomback et al (in J. Clin. Lab. Invest. 24, suppl. 107, 59, (1969)) reported thrombin inhibitors based on the amino acid sequence situated around the cleavage site for the fibrinogen ACY chain. Of the amino acid sequences discussed, these authors suggested the tripeptide sequence Phe-Val-Arg (P9-P2-P1, hereinafter referred to as the P3-P2-P1 sequence) would be the most 5 effective inhibitor.

Thrombin inhibitors based on dipeptidyl derivatives with an c~,~-aminoalkyl guanidine in the P1-position are known from US Patent N~ 4,346,078 and International Patent Application WO 93/11152. Similar, structurally related, 20 dipeptidyl derivatives have also been reported. For example International Patent Application WO 94/29336 discloses compounds with, for example, aminomethyl benzamidines, cyclic aminoalkyl amidines and cyclic aminoalkyl guanidines in the P1-position; European Patent Application 0 648 780, discloses compounds with, for example, cyclic aminoalkyl guanidines 25 in the Pl-position.

Thrombin inhibitors based on peptidyl derivatives, also having cyclic aminoalkyl guanidines (e.g. either 3- or 4- aminomethyl- 1 -amidinopiperidine) in the Pl-position are known from European Patent 30 Applications 0 468 231, 0 559 046 and 0 641 779.

Thrombin inhibitors based on tripeptidyl derivatives with arginine aldehyde in the Pl-position were f1rst disclosed in European Patent Application 0 185 390.

5 More recently, arginine aldehyde-based peptidyl derivatives, modified in the P3-position, have been reported. For example, International Patent Application WO 93/18060 discloses hydroxy acids, European Patent Application 0 526 877 des-amino acids, and European Patent Application 0 542 525 O-methyl mandelic acids in the P3-position.

Inhibitors of serine proteases (e.g. thrombin) based on electrophilic ketones in the P1-position are also known. For example, European Patent Application 0 195 212 discloses peptidyl L~-keto esters and amides, European Patent Application 0 362 002 fluoroalkylamide ketones, European Patent s Application 0 364 344 c~ -triketocompounds, and European Patent Application 0 530 167 c~-alkoxy ketone derivatives of arginine in the P1-position.

Other, structurally different, inhibitors of trypsin-like serine proteases based20 on C-terminal boronic acid derivatives of arginine and isothiouronium analogues thereof are known from European Patent Application 0 293 881.

More recently, thrombin inhibitors based on peptidyl derivatives have been disclosed in European Patent Application 0 669 317 and International Patent 2s Applications WO 95/35309, WO 95/23609 and WO 94/29336.
.

Moreover, achiral thrombin inhibitors based on aminopyridine and aminopyridazine derivatives have recently been disclosed in International Patent Applications WO 94/20467, WO 96/06832 and WO 96/06849. Other 30 achiral thrombin inhibitors have more recently been disclosed in Bioorg.

Med. Chem. Lett. 7, 1283 (1997).

However, there remains a need for effective inhibitors of trypsin-like serine proteases, such as thrombin. There is a particular need for compounds which are both orally bioavailable and selective in inhibiting thrombin over other serine proteases. Compounds which exhibit competitive inhibitory activity towards thrombin would be expected to be especially useful as anticoagulants and therefore in the therapeutic treatment of thrombosis and related disorders.

Disclosure of the Invention According to the invention there is provided a compound of formula I, R

~/ y--(CH2)n--B

wherein one of R' and R2 represents a structural fragment of formula Ia ZSO~Ar 1 la ~.~

and the other represents R4;
Z represents O or N(R5);
R3 represents one or more optional substituents selected from OH, halo, 30 cyano, nitro, C(O)OR6, C, 6alkoxy or C1 6 alkyl (which two latter groups are s optionally substituted and/or terminated by one or more halo or hydroxy group) or N(R7)R8;
R4 represents H, OH, halo, cyano, nitro, C(O)OR~, C, 6 alkoxy or Cl 6 alkyl (which two latter groups are optionally substituted and/or terminated by one 5 or more halo or hydroxy group) or N(R7)R8;
Ar~ represents phenyl, C~ 3 alkylphenyl, C1 3 alkyldiphenyl, C3 7 cycloalkyl, Cl 3-alkyl-C3 7-cycloalkyl, C, 3-alkyl-di-C3 7-cycloalkyl, naphthyl, C, 3 alkylnaphthyl, thienyl, imidazolyl or isoxazolyl, all of which may be substituted by one or more substituent selected from OH, halo, cyano, nitro, o C(O)OR6, C, 6 alkoxy or C1 6 alkyl (which two latter groups are optionally substituted and/or termin~ted by one or more halo or hydroxy group) or N(R7~R8;
R5 represents H, C1 6 alkyl, phenyl or C~ 3 alkylphenyl (which three latter groups are optionally substituted and/or terminated by one or more s substituent selected from OH, halo, cyano, nitro, C(O)OR9, C(O)N(R'~)R~', P(o)(R'2)R'3, P(o)(oR'4)oR~5~ S(o)2(R'6)R'7~ S(o)2N(Rl8)Rl9~ Cl 6alkoxyor C1-6 alkyl (which two latter groups are optionally substituted and/or termin~te~l by one or more halo or hydroxy group) or N(R20)R2l);
Y represents O, S, S(O), S(0)2 or N(R22);
20 R~~ and R" independently represent H, oR23, C(O)R24, oC(o)R25, C(O)OR26, C14 alkyl, (which latter group is optionally sub~liLul~d and/or terrnin~ted by one or more substituent selected from C14 alkyl, oR27, N(R28)R29, C(o)oR30 C(o)N(R3~)R32 P(o)(R33)R34, P(o)(oR35)oR36 and S(o)2N(R37)R38), -(CH2CH2o-)pR39 or, together with the nitrogen atom to which they are 25 attached, forrn a C47 nitrogen-cont~ining~ aromatic or non-aromatic, ring ~ which ring may contain a further heteroatom or group (as a~ opliate) selected from O, S and N(R40) and may further be substituted by one or more substituent selected from C(o)R4', C(O)oR42 or C(o)N(R43)R44;
R28, R29, R30, R3~, R32 and R40 independently represent H or C1 6 alkyl, which 30 latter group is optionally substituted and/or terminated by one or more substituent selected from C(o)R4s, C(o)oR46 or C(o)N(R47)R48;
at each occurance, R6, R7 and R8 independently represent H or C,4 alkyl;
9 12 '3 R'4 R'5 Rl6 R'7 Rl8 R'9 R20, R2', R22, R23, R24, R , R , R , R33 R34 R35 R36 R37 R38 R39 R4', R42, R43, R~, R45, R46, R47 and R
5 independently represent H or C,4 alkyl;
n represents 0, 1, 2, 3 or 4;
p represents 1, 2, 3, 4, 5 or 6; and B represents a structural fragment of formula ~b, Ic, Id or Ie ~X2 H~\NH2 HN~\NH2 H~\NH2 NH2 Ib Ic Id le wherein o X~ and x2 independently represent a single bond or CH2;
or a ph~ ceutically acceptable salt thereof (hereinafter referred to as "the compounds of the invention").

The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
All diastereoisomers may be separated using conventional techniques, e.g.
20 chromatography or fractional cryst~ tion. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds .

using conventional, e.g. fractional cryst~1~ic~tion or HPLC, techniques.
Alternatively the desired optical isomers may be made by reaction of the approp1iate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.

Alkyl groups which R3, R4, R5 R6 R7 R3 R9 Rl~ R'l Rl2 13 o R, R, R, R, R20, R2~, R22, R23, R24, R2s R26 R27 R2s R29 R30 R3~ 32 R ~ R, R, R36, R37, R38, R39, R40, R4~ R42 R43 R44 R4s R46 R47 48 may represent; the alkyl part of alkylphenyl, alkyldiphenyl, alkylcycloalkyl, alkyldicycloalkyl and alkylnaphthyl groups which Ar' may represent; the alkyl part of alkylphenyl groups which Rs may represent; and allcoxy groups 15 which R3 and R4 may represent, may be linear or branched, saturated or ~1nc~ 1rated, cyclic or acyclic. When Arl, R5, R~~ or R~ are substituted or terminated (as app-oy-iate) by alkyl or alkoxy, such substituents may be linear or branched, saturated or unsalu1ated, cyclic or acyclic.

20 Halo groups which R3 and R4 may represent include fluoro, chloro, bromo and iodo. When Ar' and Rs are substituted by halo, such substituents include fluoro, chloro, bromo and iodo.

The wavy lines on the carbon atom in the fragrnents of forrnulae Ia, Ib, Ic, 25 Id and Ie signify the bond position of the frag~nent.

Abbreviations are listed at the end of this specification.

According to a further aspect of the invention there is provided a compound 30 of formula I, as hereinbefore defined, provided that:

(a) R' represents a structural fragment of formula Ia and R2 represents R4;
(b) Arl represents optionally substituted phenyl;
(c) R5 is not substituted by P(o)(oR~4)oRIs~ S(0)2(R~6)R~7 or S(0)2N(R'8)R'9;
s (d) R'~ and/or R~l represent H or unsubstituted C,4 alkyl;
(e) Y represents 0, S or N(R5);
(f) B represents a structural fragment of formula Ib, Ic or Id.

According to a further aspect of the invention there is provided a compound o of formula I, as hereinbefore defined, provided that:
(a) R2 represents a structural fragment of formula Ia and R' represents R4;
(b) Ar' does not represent optionally substituted phenyl;
(c) Rs is substituted by P(o)(oRI4)oRls~ S(o)2(R'6)R'7 or S(0)2N(R~8)R~9;
(d) R~~ an~/or R~ do not represent H or unsubstituted C~ 4 alkyl;
(e) Y represents S(O) or S(0)2;
(f) B represents a structural fragment of for~nula Ie.

When B represents a structural fragment of formula Ib,~ Id, Ie or Ic in which latter fragment X' and x2 both represent CH2, preferred compounds of the 20 invention include those wherein n represents 2.

Preferred compounds of formula I include those wherein:
R' represents a structural fragment of formula Ia and R2 represents R4;
Z represents O or N(R5), in which latter case R5 represents C, 6 alkyl 25 substituted by C(O)N(R'~)R";
R3 is not present, or represents methyl, chloro or methoxy;
Ar' represents substituted phenyl;
Y represents O;
n represents 2;
30 B represents a structural fragment of formula Ib.
-Preferred compounds of the invention include the compounds of Examples 1 to 55.

Preparation According to the invention there is also provided a process for the preparation of compounds of formula I which comprises:

(a) reaction of a compound of formula II, ~ ,,R2 wherein Rl, R2, R3 and Y are as hereinbefore defined with a compound of formula III, L'-(CH2)n-B III
wherein L' represents a suitable leaving group (e.g. chloro, bromo, iodo, 20 mesylate, triflate or arylsulfonate) and n and B are as hereinbefore defined,for example between 0 and 100~C in the presence of a suitable base (e.g.
potassium carbonate or triethylamine) and an ap~lul~liate solvent (e.g.
acetonitrile, tetrahydrofuran or dimethylformamide);

2s (b) reaction of a compound of formula IV, . .

CA 02260l90 l998-l2-29 W 0 98/01422 PCT/SE97/OllSO

R1a ~ ,/ y - (CH2)n - B IV

wherein one of R'a and R2a represents ZH and the other represents R4, and Z, R3, R4, Y, n and B are as hereinbefore defined with a compound of o formula V, L2-SO2-Ar' V
wherein L2 is a suitable leaving group (e.g. chloro) and Arl is as hereinbefore defined, under conditions which are well known to those skilled in the art, for example in the presence of a suitable base (e.g. pyridine or 5 sodium bicarbonate) and, if ~pl-o~iate, a suitable organic solvent;

(c) for compounds of formula I in which Y represents O or S, reaction of a compound of formula VI, ,l'j/ Vl l ~' 1 wherein ya represents O or S and R~, R2 and R3 are as hereinbefore defined with a compound of formula VII, HO~(CH2)n~B VII
wherein n and B are as hereinbefore defined, for example at or below room 30 temperature in the presence of an applopliate coupling system (e.g.

.. , ... , ~ . , .

diethylazodicarboxylate and triphenylphosphine) and a suitable organic solvent (e.g. tetrahydrofuran);

(d) for compounds of formula I wherein B represents a structural fragment 5 of formula Ib or Id, reaction of a compound of formula VIII, ~ y - (CH2)n--B 1~ Vlll wherein B' represents 1,4-phenylene or 1,4-cyclohexylene and Rl, R2, R3, Y
and n are as hereinbefore defined with ammonia gas for example at room temperature in the presence of a suitable organic solvent (e.g. methanol or ethanol);

(e) for compounds of formula I wherein B represents a structural fragment of formula Ib or Id, reduction of a compound of formula IX, '5 ~'~R2 R~\Y (CH2)n B ~ IX
NOH

20 wherein Rl, R27 R3, Y, n and B~ are as hereinbefore defined in the presence of a suitable reducing agent (for example by catalytic hydrogenation in the presence of e.g. Pd/C or TiCl3) and an applu~liate organic solvent;

(f) for compounds of formula I wherein B represents a structural fragment of formula Ib or Id, reaction of a compound of formula X, R~

~ Y--(CHz)n--B1_CN X

o wherein R', R2, R3, Y, n and B' are as hereinbefore defined with arnInonium chloride, for example under reflux in the presence of a suitable catalyst (e.g.
trimethyl aluminium) and an ayplo~liate organic solvent (e.g. toluene);

(g) for compounds of formula I wherein Y represents S(O) or S(0)2, oxidation of a corresponding compound of for nula I wherein Y represents S in the presence of an ~plo~liate quantity of a suitable oxidising agent (e.g. m-chloroperbenzoic acid or sodium periodate) and an a~lo~,iate organic solvent;

20 (h) for compounds of formula I wherein Z represents N(R5) and Rs represents optionally substituted C,6 alkyl, phenyl or C,.3 alkylphenyl, reaction of a corresponding compound of formula I wherein Z represents NH
with a compound of formula XI, L2_R5a XI
25 wherein R5a represents optionally substituted C~1-6 alkyl, phenyl or C,3 alkylphenyl and L2 is as hereinbefore defined, for example in the presence of suitable base (e.g. sodium hydride or potassium carbonate) and an a~pro~liate organic solvent (e.g. DMF);

30 (i) for compounds of formula I wherein Z represents N(R5) and Rs represents C~-6 alkyl, phenyl or C,3 alkylphenyl, all of which are substituted and/or termin~te~l by C(o)N(R'3R", reaction of a corresponding compound of formula I wherein Rs represents C, 6 alkyl, phenyl or Cl3 alkylphenyl, all of which are substituted and/or termin~ted, by C(O)OR9, wherein R9 is as 5 hereinbefore defined, with a compound of formula XII, HN(R'~)R" XII
wherein R'~ and R" are as hereinbefore defined, for example (in the case where R9 represents H) in the presence of suitable a coupling system (e.g.
DCC/HOBt or EDC/HOBt) and an a~o~liate organic solvent (e.g. DMF
o or acetonitrile); or (in the case where R9 represents Cl ~ alkyl) at room temperature in the presence of an ap~ iate organic solvent (e.g. MeOH
or acetonitrile);

(1) for compounds of formula I wherein Z represents N(R5) and R5 represents s C1-6 alkyl, phenyl or C1 3 alkylphenyl, all of which are substituted and/or termin~te-l by C(O)OH, hydrolysis of a corresponding compound of formula I wherein Rs represents C~ 6 alkyl, phenyl or Cl 3 allylphenyl, all of which are substituted and/or terrnin~ted by C(O)OR9 and R9 represents C~ 1 alkyl under conditions which are well known to those skilled in the art; or (k) for compounds of formula I wherein Z represents N(R5) and R5 represents (CH2)2C(O)OR9 and R9 is as hereinbefore defined, reaction of a corresponding compound of formula I wherein Rs represents H with a compound of forrnula XIII, 2s CH2=CH-C(o)oR9 XIII
wherein R9 is as hereinbefore defined, for example by refluxing in the presence of a catalytic amount of an applo~iate organic acid (e.g. acetic acid).

30 Compounds of formulae II and VI are commercially available, are known in the literature or are available using known techniques. For example compounds of formulae II and VI may be prepared by reaction of a compound of formula XIV, R1a "' XIV
~--\YbH

wherein yb represents Y or ya as a~ pliate and R~a, R2a and R3 are as hereinbefore defined with a compound of formula V as hereinbefore defined, for example under similar conditions to those described hereinbefore for synthesis of compounds of formula I (process (b)).

Compounds of forrnulae III and VII are commercially available, are known in the literature or are available using known techniques. For example compounds of formulae III and VII wherein B represents a structural fragment of formula Ib or Id may be prepared by reaction of a 20 corresponding compound of formula XV, L3-(CH2)n-B '-C(NH)OCH2CH3 XV
wherein L3 represents L' or OH as al~pro~liate and n and B' are as hereinbefore defined with ammonia gas for example under similar conditions to those described hereinbefore for synthesis of compounds of formula I
25 (process (d)).

Compounds of formula IV may be l)le~aled by reaction of a compound of formula XIV wherein yb represents Y and Y is as hereinbefore defined with a compound of formula III as hereinbefore defined, for example under 30 similar conditions to those described hereinbefore for synthesis of compounds of formula I (process (a)).

Compounds of formula IV in which Y represents O or S may alternatively be ple~ualed by reaction of a compound of formula XIV wherein yb 5 represents ya and ya iS as hereinbefore defined with a compound of formula VII, for example under similar conditions to those described hereinbefore for synthesis of compounds of formula I (process (c)).

Compounds of formula IV in which B represents a structural ~agment of o formula Ib or Id may alternatively be prepared by reaction of a compound of formula XVI, R1a s ", y_(CH2)n--B~OcH2cH3 XVI
NH

wherein R~a, R2a, R3, Y, n and Bl are as hereinbefore defined with ammonia 20 gas for example under similar conditions to those described hereinbefore for synthesis of compounds of forrnula I (process (d)).

Compounds of formula IV in which B represents a structural fragment of formula Ib or Id may alternatively be prepal~d by reduction of a compound 25 of forrnula XVII, R1a R~3 y--(CH2)n B ~ XVII
NOH

wherein R'a, R2a, R3, Y, n and B' are as hereinbefore defined, under similar conditions to those described hereinbefore for synthesis of compounds of o formula I (process (e)).

Compounds of formulae VIII, XV and XVI may be prepared by reaction of a corresponding cyanobenzene of fonnula X as hereinbefore defined (for a compound of formula VIII), a corresponding cyanobenzene of formula 5 XVIII, L3-(CH2)n-B l-CN XVIII
wherein L3, n and B' are as hereinbefore defined (for a compound of formula XV), or a corresponding cyanobenzene of formula XIX, R1a ~ R 2a ,/ Y (CH2)n B 1 CN XIX

25 wherein R'a, R2a, R3, Y, n and B ' are as hereinbefore defined (for a compound of forrnula XVI), with HCl(g) and ethanol, for example at or below room temperature (e.g. 0~C).

Compounds of formula IX and XVII may be prepared by reaction of a 30 compound of formula X or XIX as hereinbefore defined (as appropriate) . _ _ .. .. .. .

CA 02260l90 l998-l2-29 with hydroxylamine, for example at or around 40~C in the presence of a suitable base (e.g. triethylamine) and an a~plo~liate organic solvent (e.g.
ethanol).

5 Compounds of formula X may be prepared by reaction of a compound of formula XIX as hereinbefore defined with a compound of formula V as hereinbefore defined for example under similar conditions to those described hereinbefore for synthesis of compounds of formulae I (process (b)), II and VI.

Compounds of formula X may alternatively be prepared by reaction of a compound of formula II as hereinbefore defined with a compound of formula XX
L ~ -(CH2)n-B I -CN XX
wherein L~, n and B~ are as hereinbefore defined, for example under similar conditions to those described hereinbefore for synthesis of compounds of formula I (process (a)).

Compounds of formula X wherein Y represent O or S may alternatively be 20 prepared by reaction of a compound of formula VI as hereinbefore defined with a compound of formula XXI
HO-(CH2)n-B '-CN XXI
wherein n and B' are as hereinbefore defined, for example under similar conditions to those described hereinbefore for synthesis of compounds of 25 formula I (process (c)).

Compounds of formula XIX may be prepared by reaction of a compound of - formula XIV wherein yb represents Y and Y is as hereinbefore defined with a compound of formula XX as hereinbefore defined, for example under 30 similar conditions to those described hereinbefore for synthesis of -compounds of formula I (process (a)).

Compounds of formula XIX wherein Y represents O or S may be prepared by reaction of a compound of formula XIV wherein yb represents ya and ya 5 iS as hereinbefore defined with a compound of formula XXI as hereinbefore defined, for example under similar conditions to those described hereinbefore for synthesis of compounds of formula I (process (c)).

Compounds of formulae II, IV, VI, VIII, IX, X, XIV, XVI, XVII and XIX
o wherein Z represents N(R5) and R5 represents optionally substituted C,.6 alkyl, phenyl or Cl3 alkylphenyl, may be prepared by reaction of a corresponding compound of formula II, IV, VI, VIII, IX, X, XIV, XVI, XVII or XIX (as ap~lo~liate) wherein Z represents NH with a compound of formula XI as hereinbefore defined, for example under similar conditions to 15 those described hereinbefore for synthesis of compounds of formula I
(process (h)).

Compounds of formulae II, IV, VI, VIII, IX, X, XIV, XVI, XVII and XIX
wherein Z represents N(R5) and Rs represents Cl 6 alkyl, phenyl or Cl3 20 alkylphenyl substituted and/or termin~te~l, in all three cases, by C(O)N(R~~)R~ may alternatively be l.lel)aled by reaction of a corresponding compound of formula II, IV, VI, VIII, IX, X, XIV, XVI, XVII or XIX (as ap~olo~,iate) wherein R5 represents C~ 6 alkyl, phenyl or Cl3 alkylphenyl substituted and/or terminated, in all three cases, by C(O)OR9, wherein R9 is 2s as hereinbefore defined, with a compound of formula XII as hereinbefore defined, for example under similar conditions to those described hereinbefore for synthesis of compounds of formula I (process (i)).

Compounds of formulae II, IV, VI, VIII, IX, X, XIV, XVI, XVII and XIX
30 wherein Z represents N(R5) and R5 represents C,.6 alkyl, phenyl or Cl3 .. . ..

CA 02260l90 l998-l2-29 alkylphenyl substituted and/or terminated, in all three cases, by C(O)OH may alternatively be prepared by hydrolysis of a corresponding compound of formula II, IV, VI, VIII, IX, X, XIV, XVI, XVII or XIX (as ap~lop~iate) wherein R5 represents C~ 6 alkyl, phenyl or Cl3 alkylphenyl substituted 5 and/or termin~ted, in all three cases, by C(o)oR9 and R9 represents C~4 alkyl under conditions which are well known to those skilled in the art.

Compounds of formulae II, IV, VI, VIII, IX, X, XIV, XVI, XVII and XIX
wherein Z represents N(R5) and R5 represents (CH2)2C(O)OR9 and R9 is as 10 hereinbefore defined, may alternatively be ~rcpaled by reaction of a corresponding compound of forrnula II, IV, VI, VIII, IX, X, XIV, XVI, XVII or XIX (as a~p~ iate) wherein Rs represents H with a compound of formula XIII as hereinbefore defined, for example under similar conditions to those described hereinbefore for synthesis of compounds of formula I
(process (k)).

Compounds of formulae V, XI, XII, XIII, XIV, XVIII, XX and XXI are either commercially available, are well known in the literature, or are available using known techniques. For example compounds of formula XIV
20 wherein Rla and/or R2a represent NH2 may be prepared by reduction of the corresponding nitrobenzene under conditions which are well known to those skilled in the art. Similarly, compounds of formula XIV wherein R'a and/or R2a represent OH may be prepared by hydrolysis of a corresponding alkoxybenzene under conditions which are well known to those skilled in the 25 art. Compounds of formulae IV, XVI, XVII and XIX wherein Rla and/or R2a represent NH2 or OH may also be ~re~alcd from the corresponding nitrobenzene or alkoxybenzene (as a~plo~liate) in accordance with these techniques.

30 Substituents on the aromatic and/or non-aromatic, carbocyclic and/or heterocyclic ring(s) in compounds of formulae I, II, IV, V, VI, VIII, IX, X, XI, XII, XIV, XVI, XVII and XIX may be interconverted by techniques well known to those skilled in the art.

5 The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.

It will be appreciated by those skilled in the art that in the process describedabove the functional groups of intermediate compounds may need to be o protected by protecting groups.

Functional groups which it is desirable to protect include hydroxy, amino, amidino, guanidino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. t-s butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for hydroxy groups, which groups are attached to adjacent carbon atoms include O,O'-isopropylidene.
Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl or benzyloxycarbonyl. Amidino and guanidino nitrogens 20 may be either mono- or diprotected. Suitable protecting groups for carboxylic acid include C, 6 alkyl or benzyl esters.

The protection and deprotection of functional groups may take place before or after a reaction step.

Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.

The use of protecting groups is fully described in "Protective Groups in 30 Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 2nd edition, T W Greene & P G
M Wutz, Wiley-Interscience (1991).

It will also be appreciated by those skilled in the art that, 'protected 5 derivatives" of compounds of formula I may be formed prior to a final deprotection step. Although they may not possess pharmacological activity as such, certain "protected derivatives" of compounds of formula I may be ~lmini~tered parenterally or orally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such o derivatives may therefore be described as "prodrugs". All prodrugs of compounds of formula I are included within the scope of the invention.

Medical and pharmaceutical use 15 The compounds of the invention are useful because they possess phannacological activity. They are therefore indicated as pharmaceuticals.

According to a further aspect of the invention there is thus provided the compounds of the invention for use as ph~ ceuticals.

In particular, the compounds of the invention are potent inhibitors of thrombin for example as demonstrated in the tests described below.

The compounds of the invention are thus expected to be useful in those 25 conditions where inhibition of thrombin is required.

The compounds of the invention are thus indicated in the treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues of ~nim~ including man.

CA 02260l90 l998-l2-29 It is known that hypercoagulability may lead to thrombo-embolic diseases.
Conditions associated with hypercoagulability and thrombo-embolic diseases which may be mentioned include activated protein C resistance, such as the factor V-mutation (factor V Leiden), and inherited or ac~uired deficiencies in antithrombin III, protein C, protein S, heparin cofactor II. Other conditions known to be associated with hypercoagulability and thrombo-embolic disease include circulating antiphospholipid antibodies (Lupus anticoagulant), homocysteinemi, heparin induced thrombocytopenia and defects in fibrinolysis. The compounds of the invention are thus indicated o both in the therapeutic and/or prophylactic treatment of these conditions.

The compounds of the invention are further indicated in the treatment of conditions where there is an undesirable excess of thrombin without signs of hypercoagulability, for example in neurodegenerative diseases such as 5 Alzheimer's disease.

Particular disease states which may be mentioned include the therapeutic and/or prophylactic treatment of venous thrombosis and pulmonary embolism, arterial thrombosis (eg in myocardial infarction, unstable angina, 20 thrombosis-based stroke and peripheral arterial thrombosis) and systemic embolism usually from the atrium during arterial fibrillation or from the left ventricle after transmural myocardial infarction.

Moreover, the compounds of the invention are expected to have utility in 25 prophylaxis of re-occlusion (ie thrombosis) after thrombolysis, percutaneous trans-luminal angioplasty (PTA) and coronary bypass operations; the prevention of re-thrombosis after microsurgery and vascular surgery in general.

30 Further indications include the therapeutic and/or prophylactic treatment of W 0 98/01422 PCT/SE97tO1150 dissemin~te~l intravascular coagulation caused by bacteria, multiple trauma, intoxication or any other mech~ni~m; anticoagulant treatment when blood is in contact with foreign surfaces in the body such as vascular grafts, vascular stents, vascular catheters, mechanical and biological prosthetic valves or any 5 other medical device; and anticoagulant treatment when blood is in contact with medical devices outside the body such as during cardiovascular surgery using a heart-lung machine or in haemodialysis.

In addition to its effects on the coagulation process, thrombin is known to o activate a large number of cells (such as neutrophils, fibroblasts, endothelial cells and smooth muscle cells). Therefore, the compounds of the invention may also be useful for the therapeutic and/or prophylactic treatment of idiopathic and adult respiratory distress syndrome, pulmonary fibrosis following treatment with radiation or chemotherapy, septic shock, 5 septicemia, infl~mm~tory responses, which include, but are not limited to, edema, acute or chronic atherosclerosis such as coronary arterial disease, cerebral arterial disease, peripheral arterial disease, reperfusion damage, and restenosis after percutaneous trans-luminal angioplasty (PTA).

20 Compounds of the invention that inhibit trypsin andlor thrombin may also be useful in the treatment of pancreatitis.

According to a further aspect of the present invention, there is provided a method of treatment of a condition where inhibition of thrombin is required 25 which method comprises ~tlmini.~tration of a therapeutically effective amountof a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person suffering from, or susceptible to such a condition.

The compounds of the invention will normally be ~ministered orally, 30 intravenously, subcutaneously, buccally, rectally, derrnally, nasally, -- , . . . .

W 0 98/01422 PCT/SE97/OllSO

tracheally, bronchially, by any other parenteral route or via inhalation, in theform of pharmaceutical preparations comprising active compound either as a free base, or a pharmaceutical acceptable non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of ~(imini.ctration, the compositions may be ~lrnini.~tered at varying doses.

The compounds of the invention may also be combined andlor co-administered with any anliLh-olllbotic agent with a different mech~ni.cm of o action, such as the antiplatelet agents acetylsalicylic acid, ticlopidine, clopidogrel, thromboxane receptor and/or synthetase inhibitors, fibrinogen receptor antagonists, prostacyclin mimetics and phosphodiesterase inhibitors and ADP-receptor (P2T) antagonists.

~5 The compounds of the invention may further be combined and/or co-~lmini~tered with thrombolytics such as tissue plasminogen activator (natural, recombinant or modified), streptokinase, urokinase, prourokinase, anisoylated plasminogen-streptokinase activator complex (APSAC), animal salivary gland plasminogen activators, and the like, in the treatment of 20 thrombotic diseases, in particular myocardial infarction.

According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Suitable daily doses of the compounds of the invention in therapeutical treatment of humans are about 0.001-100 mg/kg body weight at peroral ~1mini~tration and 0.001-50 mg/kg body weight at parenteral a-lmini.ctration.

30 The compounds of the invention have the advantage that they may be more ... ... .. . ....

efficacious, be less toxic, be longer acting, have a broader range of activity, be more potent, produce fewer side effects, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art.
s Biological Tests Test A
Determination of Thrombin clotting Time (TT) o Human thrombin (T 6769, Sigma Chem. Co) in buffer solution, pH 7.4, 100 ~1, and inhibitor solution, 100 ,ul, were incubated for one minute. Pooled normal citrated human plasma, 100 ,1l1, was then added and the clotting time measured in an automatic device (KC 10, Arnelung).

5 The clotting time in seconds was plotted against the inhibitor concentration, and the IC50TT was determined by interpolation.

IC50TT is the concentration of inhibitor in the test that doubles the thrombin clotting time for human plasma.

Test B
Dete",~i"~ton of thrombin inhibition with a chromogenic~ robotic assay.
The thrombin inhibitor potency was measured with a chromogenic substrate method, in a Plato 3300 robotic microplate processor (Rosys AG, CH-8634 25 Hombrechtikon, Switzerland), using 96-well, half volume microtitre plates (Costar, Cambridge, MA, USA; Cat No 3690). Stock solutions of test substance in DMSO (72 IlL), 1 mmol/L, were diluted serially 1 :3 (24 + 48 ~,lL) with DMSO to obtain ten different concentrations, which were analysed as samples in the assay. 2 IlL of test sample was diluted with 124 ~lL assay 30 buffer, 12 ~L of chromogenic substrate solution (S-2366, Chromogenix, Molndal, Sweden) in assay buffer and finally 12 ~lL of cY-thrombin solution, (Human a~-thrombin, Sigma Chemical Co.) both in assay buffer, were added, and the samples mixed. The final assay concentrations were: test substance 0.00068 - 13.3 llmol/L, S-2366 0.30 mmol/L, o~-thrombin 0.020 NIHU/mL.
5 The linear absorbance increment during 40 minutes incubation at 37~C, was used for calculation of percentage inhibition for the test samples, as compared to blanks without inhibitor. The IC50-robotic value, corresponding to the inhibitor concentration which caused 50% inhibition of the thrombin activity, was calculated from a log dose vs. % inhibition curve.

Test C
Determinaton of the inhibition constant ~ for human thrombin ~-determin~tions were made using a chromogenic substrate method, performed at 37~C on a Cobas Bio centrifugal analyser (Roche, Basel~
Switzerland). Residual enzyme activity after incubation of human ~-thrombin with various concentrations of test compound was determined at three different substrate concentrations, and was measured as the change in optical absorbance at 405 nm.

20 Test compound solutions (100 IlL; normally in buffer or saline containing BSA 10 g/L) were mixed with 200 IlL of human cx-thrombin (Sigma Chemical Co) in assay buffer (0.05 mol/L Tris-HCl pH 7.4, ionic strength 0.15 adjusted with NaCl) containing BSA (10 g/L), and analysed as samples in the Cobas Bio. A 60 ~lL sample, together with 20 ~L of water, was 25 added to 320 ~L of the substrate S-2238 (Chromogenix AB, Molndal, Sweden) in assay buffer, and the absorbance change (~A/min) was monitored. The final concentrations of S-2238 were 16, 24 and 50 ~lmol/L
and of thrombin 0.125 NIH U/ml.

30 The steady state reaction rate was used to construct Dixon plots, i.e.

W O 98/01422 PCT/SE97/OllS0 diagrams of inhibitor concentration vs. 1/(~AJmin). For reversible, competitive inhibitors, the data points for the different substrate concentrations typically forrn straight lines which intercept at x = -~.

s Test D
Determination of Activated Partial Thromboplastin Time (APTT) APTT was d~le~ ined in pooled normal human citrated plasma with the reagent PTT Automated 5 manufactured by Stago. The inhibitors were added to the plasma (10 ~LL inhibitor solution to 90 ,uL plasma) followed by the o reagent and calcium chloride solution and APTT was determined in the mixture by use of the coagulation analyser KC10 (Amelung) according to the instructions of the reagent producer. The clotting time in seconds was plotted against the inhibitor concentration in plasma and the IC50APTT was determined by interpolation.

IC50APTT is defined as the concentration of inhibitor in human plasma that doubled the Activated Partial Thromboplastin Time.

Test E
20 Deterrnin~ion of thrombin time ex vivo The inhibition of thrombin after oral or parenteral ~iministration of the compounds of the invention were examined in conscious rats which, one or two days prior to the experiment, were e~uipped with a catheter for blood sampling from the carotid artery. On the experimental day blood samples 25 were withdrawn at fixed times after the ~1mini~tration of the compound into plastic tubes containing l part sodium citrate solution (0.13 mol per L) and 9 parts of blood. The tubes were centrifuged to obtain platelet poor plasma.
The plasma was used for determination of thrombin time as described above.

30 The citrated rat plasma, 100 ,uL, was diluted with a saline solution, 0.9%, 100 ,uL, and plasma coagulation was started by the addition of human thrombin (T 6769, Sigma Chem Co, USA) in a buffer solution, pH 7.4, 100 ,uL. The clotting time was measured in an automatic device (KC lO, Amelumg, Germany).

The invention is illustrated by way of the following examples.

Examples o General Experimental Procedures.
Mass spectra were recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer equipped with an electrospray interface (FAB-MS) and VG Platform II mass spectrometer equipped with an electrospray interface (LC-MS). lH NMR and 13C NMR measurements were performed on lS BRUKER ACP 300 and Varian UNITY plus 400, 500 and 600 spectrometers, operating at 'H fre~uencies of 300.13, 399.96, 499.82 and 599.94 MHz respectively, and at 13C frequencies of 75.46, 100.58, 125.69 and 150.88 MHz respectively. Flash chromatography was carried out on silica gel (230-400 mesh). Pre~al~tive HPLC was performed on reverse 20 phase columns (250 mm, 20 or 50 mm; 5 to 7 ,uM phase Chromasil C8) with flow rates of 10 to 50 mL/min using a W detector (270 to 280 nm).

Example 1 N- { 3 - [2-(4-Aminoiminomethylphenyl!ethoxyJphenyl } benzenesulfonamide 2s x HCl (i) t-Butyloxycarbonylamino-3-hydroxybenzene Amino-3-hydroxybenzene (5.46 g; 50 mmol) was dissolved in THF (50 mL) and di-t-butyl dicarbonate (12.0 g; 55 mmol) was added at room 30 temperature. The solution was heated for 2 hours at 60~C, the solvent was evaporated and the residue was dissolved in EtOAc (150 mL). The EtOAc-phase was washed with 2 x 20 mL of lM KHS04, 1 x 20 mL water, 1 x 20 mL br~ne and then dried (MgS04). The solvent was evaporated to give 11.74 g of a colourless oil which was crystallised from CH2Cl2:MeOH:light 5 petroleum to give 9.1 g (87%) of the sub-title compound as white crystals.

'H-NMR (400 MHz; CDC13): ~ 7.10-7.15 (bs, IH), 7.11 (t, lH), 6.72 (dd, lH), 6.53 (dd, lH), 6.50 (bs, lH), 5.57 (apparent bs, lH), 1.52 (s, 9H~
'3C-NMR (100 MHz; CDCl3): ~ 156.4, 152.8, 139.4, 129.9, 110.7, 110.2, o 105.9, 80.8, 28.3 (ii) t-Butyloxycarbonylamino-3-~2-(4-cyanophenyl)ethoxy]benzene To a solution of t-butyloxycarbonylamino-3-hydro~cybenzene (418.5 mg; 2 mmol; from step (i) above), triphenylphosphine (629.5 mg; 2.4 mmol) and s 2-(4-cyanophenyl)ethanol (353.2 mg; 2.4 mmol) in THF (50 mL), under an atmosphere of nitrogen, was added diethylazodicarboxylate (518 mg; 3 rnmol) and the mixtur~ was stirred for one week. Ice cold water was added and the THF was removed by evaporation. The rem~ining water phase was extracted three times with EtOAc. The combined organic phase was washed 20 twice with 0.2 M NaOH, once with brine, and then dried (Na2SO4).
Evaporation followed by flash chromatography using a stepwise gradient of toluene:EtOAc (100:0, 90:10, 80:20 and 60:40) gave 300 mg (44%) of the sub-title compound.

~s 'H-NMR (300 MHz; CDCI3): ~ 7.57 (d, 2H), 7.37 (d, 2H), 7.21 (bs, lH), 7.14 (t, lH), 6.76 (dd, lH), 6.67 (bs, lH, NH), 6.54 (dd, lH), 4.16 (t, 2H), 3.10 (t, 2H), 1.50 (s, 9H) 3C-NMR (75 MHz; CDCl3): ~ 159.05, 152.57, 144.17, 139.65, 132.05, 129.74, 129.52, 118.84, 110.82, 110.14, 109.10, 104.52,80.41,67.43,35.65, 30 28.20 . .

CA 02260l90 l998-l2-29 (iii) Amino-3-~2-(4-cYanophenYl)ethoxy~benzene x HCI
t-Butyloxycarbonylamino-3-[2-(4-cyanophenyl)ethoxy]benzene (300 mg; 0.89 mmol; from step (ii) above) was dissolved in EtOAc, pre-saturated with HCl(g), at room temperature and stirred for 1 hour. The solvent and the excess HCl(g) was evaporated to give 231 mg (94%) of the sub-title compound.

IH-NMR (400 MHz; CD30D): ~ 7.66 (d, 2H), 7.50 (d, 2H), 7.40 (t, IH), 7.01 (bd, lH), 6.90 (bd, lH), 6.85 (bs, lH), 4.28 (t, 2H), 3.18 (t, 2H) (iv) N-{3-[2-(4-Cyanophenyl)ethoxylphenyl}benzenesulfonamide To a cold (ice:water temperature) solution of amino-3-[2-(4-cyanophenyl)ethoxy]benzene x HCI (231 mg; 0.84 mmol; from step (iii) above) in pyridine (2 rnL) was added benzenesulfonyl chloride (119 f~L;
5 0.93 mmol) and the mi~lu-e was allowed to reach room temperature and stirTed for three days. The pyridine was removed by evaporation and the residue was partitioned between water and EtOAc. The phases was separated and the water phase was extracted twice with EtOAc and the combined organic phase was washed once with lM KHSO4, brine and dried 20 (Na2SO4). The solvent was evaporated and the residue was subjected to purification by flash chromatography using a stepwise gradient of toluene:EtOAc (100:0, 90:10, 80:20, 60:40 and 40:60) as eluent to give 277 mg (87%) of the sub-title compound.

25 LC-MS 377 (M - 1)-~H-NMR (400 MHz; CDCl3): ~ 7.82 (d, 2H), 7.75 (bs, lH, NH), 7.56 (d, 2H), 7.47-7.53 (m, lH), 7.40 (t, 2H), 7.35 (d, 2H), 7.07 (t, lH), 6.75 (bt, lH), 6.65-6.70 (m, lH), 6.59 (dd, lH), 4.10 (t, 2H), 3.07 (t, 2H) (v) N-~3-~2-(4-Ethoxyiminomethylphenyl)ethoxylphenyl3berlzenesulfonamide x HCl A gentle stream of HCl(g) was passed into a cooled (0~C) solution of N- {3-[2-(4-cyanophenyl)ethoxy]phenyl}benzenesulfonamide (257 mg; 0.68 mmol;
from step (iv) above) in absolute EtOH (10 mL) until the temperature was stabilized at 0~C. The mixture was allowed to reach room temperature and stirred at this temperature for 24 hours. The solvent was evaporated to give the sub-title compound in a quallliLaLi~re yield.

10 ~H-NMR (600 MHz; CD30D): ~ 7.96 (d, 2H), 7.70-7.73 (m, 2H), 7.55 (d, 2H), 7.50-7.54 (m, lH), 7.43 (t, 2H), 7.03 (t, lH), 6.67 (t, lH), 6.56 (dd, 2H), 4.60 (q, 2H), 4.15 (t, 2H), 3.14 (t, 2H), 1.59 (t, 3H) (vi) N- {3-t2-(4-Aminoiminomethylphenyl)ethoxylphenyl } benzene-s sulfonamide x HCI
N- {3-[2-(4-Ethoxyiminomethylphenyl)ethoxy]phenyl} benzenesulfonamide x HCI (313 mg; 0.68 mmol; from step (v) above) was dissolved in methanol, saturated with ammonia gas and stirred at room temperature for three days.
A precipitate had formed and, after addition of 0.5 mL Et2O, the mixture 20 was place in a freezer overnight. The precipitate was collected by filtration and the filter-cake was washed with cool MeOH (1 mL) and Et2O (3 mL).
The crystals were dried and added to MeOH (8 mL) to form a slu~Ty.
MeOH saturated with HCl(g) was added until the solution became clear and the volume was concentrated to give 2-3 mL. Addition of Et2O (20 mL) 25 caused a precipitate to form which was filtered and dried under vacuum to yield 169 mg (57%) of the title compound.

FAB-MS 396 (M + l)+
IH-NMR (400 MHz; CD30D): ~ 9.20 (bs, 1 H, NH), 8.71 (bs, lH, NH), 30 7.72-7.77 (m, 4H), 7.51-7.57 (m, 3H), 7.42-7.49 (m, 2H), 7.05 (t, lH), 6.70 CA 02260190 l998-l2-29 (t, lH), 6.56-6.62 (m, 2H), 4.16 (t, 2H), 3.14 (t, 2H) '3C-NMR (100 MHz; CDC13): ~ 160.64, 147.36, 147.02, 141.04, 140.14, 133.89, 131.14, 130.93, 130.01, 12~.99, 128.16, 114.49, 111.83, 108.52, 69.00, 36.38 s Example 2 Benzenesulfoni~cid- {3 - ~2-(4-aminoiminomethylphenyl)ethoxyl-5 -methyl } -phenyl ester x HCI

o (i) Benzenesulfonic acid-(3-hydroxy-5-methyl)phenyl ester Benzenesulfonyl chloride (6.36 g; 36 mmol) was added to a well stirred mixture of 3,5-dihydroxytoluene x H2O (4.26 g; 30 mmol), saturated aqueous NaHCO3 (70 mL) and Et2O (50 mL) and the mixture was stirred at room temperature for 19 hours. Et2O (50 mL) was added and the organic 5 layer was separated, collected and evaporated to give 7.05 g of a powder.
The crude material was recrystallized from EtOAc:heptane (30 mL:300 mL) to give 4.36 g (55%) of the sub-title compound.

FAB-MS 265 (M + 1)+
~H-NMR (400 MHz; CDCl3): ~ 7.86 (d, 2H), 7.67 (tt, lH), 7.53 (t, 2H), 6.54 (bs, lH), 6.38 (bs, lH), 6.31 (t, lH), 5.02 (s, lH, OH), 2.21 (s, 3H) (ii) Benzenesulfonic acid- {3-~2-(4-cyanophenyl)ethoxy~-5-methyl}phenyl ester 25 Diethylazodicarboxylate (1.74 g; 10 mmol) was added, over 5 minutes, to a stirred solution of triphenylphosphine (2.62 g; 10 mmol), 2-(4-cyanophenyl)ethanol (1.47 g; 10 mmol) and benzenesulfonic acid-(3-hydroxy-5-methyl)-phenyl ester (2.64 g; 10 mmol; from step (i) above) in THF (25 mL) at room temperature. The stirring was continued for an 30 additional 17 hours, the THF was evaporated and the residue was dissolved in EtOAc (150 mL). The organic phase was washed with 2 x 25 mL of lM
NaOH, l x 25 mL of lM KHSO4, 1 x 10 mL of brine and dried (MgSO4).
The solvent was evaporated to give 9.09 g of an oil. Purification by flash chromatography using a stepwise gradient oftoluene:EtOAc (100:0, 20: 1 and 10:1) gave 2.79 g (71%) of the sub-title compound as a white powder.

FAB-MS 394 (M + 1)+
~H-NMR (400 MHz; CDCl3): ~S 7.85 (apparent dd, 2H), 7.66 (tt, IH), 7.60 (apparent d, 2H), 7.50-7.55 (m, 2H), 7.35 (d, 2H), 6.57 (bs, lH), 6.35-6.38 o (m, 2H), 4.07 (t, 2H), 3.08 (t, 2H), 2.21 (s, 3H) (iii) Benzenesulfonic acid- {3-[2-(4-ethoxyiminomethylphenyl)ethoxy} -5-methyl}phenyl ester x HCl EtOH (25 mL) was cooled to 5~C and a gentle stream of HCl(g) was 5 bubbled through until saturation. Benzenesulfonic acid- {3-~2-(4-cyanophenyl)ethoxy]-5-methyl}phenyl ester (590 mg; 1.5 mmol; from step (ii) above) was added to the cold solution in one portion and the mixture was allowed to reach room temperature and stirred over night. The solvent and excess HCl(g) was evaporated to give the sub-title compound in a 20 quantitative yield.

IH-NMR (400 MHz; CD30D): ~ 7.99 (apl)arellt d, 2H), 7.81 (apparent d, 2H), 7.72 (dt, lH), 7.53-7.62 (m, 4H), 6.63 (bs, lH), 6.34 (bs, lH), 6.30 (a~arellt t, lH), 4.63 (q, 2H), 4.13 (t, 2H), 3.14 (t, 2H), 2.18 (s, 3H), 1.61 25 (t, 3H) (iv) Benzenesulfonic acid- {3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methyl~phenyl ester x HCl Benzenesulfonic acid- {3-[2-(4-ethoxyiminomethylphenyl)ethoxy]-5-30 methyl}phenyl ester x HCl (1.5 mmol; from step (iii) above) was dissolved in MeOH pre-saturated by ammonia and the reaction was stirred at room temperature for 24 hours. The solvent and excess ammonia were evaporated and the residue was dissolved in MeOH (5 mL). 6 mL of 1.77 M HCl(g) in MeOH~was added and the solution was concentrated to about 3 mL. Et2O
(60 mL) was added to precipitate the hydrochloride salt of the title compound. The volume was reduced to 45 mL and the mixture was placed in a freezer for two days. Collection of the precipitate by filtration followed by drying under vacuum gave 575 mg (86%; calculated from the nitrile above) of the pure title compound as a white powder.

FAB-MS 411 (M + 1)+
'H-NMR (400 MHz; CD30D): ~ 7.79-7.83 (m, 2H), 7.70-7.77 (m, 3H), 7.58 (apparent t, 2H), 7.52 (d, 2H), 6.63 (bs, lH), 6.34 (bs, lH), 6.29 (bs, lH), 4.11 (t, 2H), 3.11 (t, 2H), 2.18 (s, 3H) Example 3 N- {3-[2-(4-Aminoiminomethylphenyl)ethoxy~phenyl} -2-chlorobenzenesulfonamide x HOAc 20 (i) Nitro-3-~2-(4-cyanophenyl)ethoxy]benzene Triphenylphosphine (11.3 g; 43.1 mmol) and diethylazodicarboxylate (7.5 g; 43 mmol) were dissolved in THF (250 mL) under nitrogen at 0~C. After 5 minutes, 3-nitrophenol (5.00 g; 35.9 mmol) and 2-(4-cyanophenyl)ethanol - (6.3 g; 43 mmol) were added. The cooling bath was removed and the 2s mixture stirred for 2 days at room temp~ldlu.e. A new batch was prepared as above and the two were combined before work-up. Water was added and the THF was evaporated. The mixture was extracted with EtOAc, and the organic phase was washed with a~ueous 0.2M NaOH and brine, dried (Na2SO4) and the solvent removed in vacuo. Purification by flash 30 chromatography (SiO2; toluene) and recryst~lli7~tion from CH2CI2:EtOH

afforded 3.07 g (32%) of the sub-title compound.

'H NMR (500 MHz; CDC13): ~ 7.82 (dd, lH), 7 61-7.71 (several peaks, 4H), 7.41 (d, 2H), 7.19 (dd, lH), 4.27 (t, 2H), 3.19 (t, 2H) s (ii) Amino-3-~2-(4-cyanophenYl)ethoxYlbenzene Nitro-3-[2-(4-cyanophenyl)ethoxy]benzene (3.0 g; 11.2 mmol; from step (i) above) and NH4Cl (2.9 g; 55 mrnol) were dissolved in a nli~Lule of EtOH
(40 rnL) and H20 (10 mL) and heated to reflux. Iron powder (3.0 g; 55 o mmol) was added and he~ting was continued for l hour. The nli~lule was filtered, concentrated in vaCuo and partitioned between water and CH2Cl2.
After separation, the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (MgSO4) and the solvent was evaporated. Purification by flash chromatography (SiO2; toluene:EtOAc 5 (9:1)) afforded 2.26 g (85%) of the sub-title compound.

LC-MS 239 (M + 1)+
~H NMR (300 MHz; CDCl3): ~ 7.59 (d, 2H), 7.39 (d, 2H), 7.05 (t, lH), 6.32 (m, 2H), 6.24 (t, lH), 4.15 (t, 2H), 3.12 (t, 2H), 2.0 (s, 2H) (iii) N-{3-~2-(4-Cvanophenvl)ethoxy7phenyl}-2-chlorobenzenesulfonamide Pyridine (0.255 mL; 3.15 mrnol) was added to a stirred solution of amino-3-[2-(4-cyanophenyl)ethoxy~benzene (0.15 g; 0.629 mmol; from step (ii) above) and 2-chlorobenzenesulfonyl chloride (0.173 mL; 0.818 mrnol) in 25 CH2Cl2 (4 mL). After 45 minutes at room temperature the solvent was removed in vacuo. To remove traces of pyridine, EtOH was added and evaporated. The residue was partitioned between water and EtOAc. The organic layer was washed with 0. lM aqueous HCl and brine, dried (Na~SO4) and the solvent removed in vaCuo. Purification by flash chromatography 30 (siO2; toluene:EtOAc (1:0 to 9:1)) afforded 0.095 g (35%) of the sub-title . ~

W O 98/01422 PCT/SE97/OllSO

compound.

'H NMR (400 MHz; CD30D): ~ 8.02 (dd, lH), 7.62 (d, 2H), 7.45-7.52 (several peaks, 2H), 7.32-7.40 (several peaks, 3H), 7.09 (m, 2H), 6.75 (t, lH), 6.65 (dd, lH), 6.59 (dd, lH), 4.13 (t, 2H), 3.11 (t, 2H) (iv) N-{3-[2-(4-Ethoxyiminomethylphenyl)ethoxylphenyl}-2-chloro-benzenesulfonamide x HCI
N- {3-[2-(4-Cyanophenyl)ethoxy]phenyl3 -2-chlorobenzenesulfonamide o (0.070 g; 0.163 mmol; from step (iii) above) was added to a saturated solution of HCl(g) in EtOH (100 mL) and the solution stirred for 24 hours.
Evaporation of the solvent afforded the sub-title compound in a quantitative yield.

5 LC-MS 459 (M + 1)+

(v)N- {3-[2-(4-Arninoiminomethylphenyl)ethoxvlPhenyl } - 2-chlorobenzene-sulfonamide x HOAc N- {3-[2- (4-Ethoxyiminomethylphenyl)ethoxy]phenyl} -2-chlorobenzene-20 sulfonamide x HC1 (0.080 g, 0.16 mmol; from step (iv) above) was dissolved in MeOH (pre-saturated with NH3(g)) and stirred at room temperature for 1 day. The solvent was evaporated and the residue purified by preparative HPLC (40% CH3CN:0.1 M NH40Ac) to afford 0.020 g (25%) of the title compound.

LC-MS 430 (M + 1)+
'H NMR (400 MHz; CD30D): ~ 8.02 (dd, lH), 7.73 (d, 2H), 7.50-7.55 (several peaks, 4H), 7.38 (m, lH), 7.04 (t, lH), 6.70 (t, lH), 6.65 (m, lH), 6.59 (m, lH), 4.14 (t, 2H), 3.13 (t, 2H), 1.90 (s, 3H) , ~

W 0 98/01422 PCTtSE97/OllSO

Example 4 N- {3- ~2-(4-Aminoiminomethylphenyl)ethoxylphenyl } -2-cyanobenzene-sulfonamide x HCI

s (i) 3-~2-(4-Ethoxyiminomethylphenyl)ethoxy~nitrobenzene x HCl A gentle stream of HCl(g) was passed into a cooled (NaCl:ice) suspension of nitro-3-[2-(4-cyanophenyl)ethoxy]benzene (2.80 g; 10.4 mmol; from Example 3(i) above) in EtOH (200 rnL) until the temperature was stabilized at 0~C. After 3.5 hours stirring the temperature was allowed to rise to o ambient and the stirring was continued for 24 hours. Evaporation of the solvent in vacuo gave the sub-title compound in a quantitative yield.

IH NMR (400 MHz; CD30D): ~ 8.00 (d, 2H), 7.80 (ddd, lH), 7.70 (t, lH), 7.63 (d, 2H), 7.48 (t, lH), 7.30 (ddd, lH), 4.62 (q, 2H), 4.38 (t, 2H), 3.28 l5 (t, 2H), 1.60 (t, 3H) (ii) 3-~2-(4-Aminoiminomethylphenyl)ethoxy~nitrobenzene x HCl 3-[2-(4-Ethoxyiminomethylphenyl)ethoxy]nitrobenzene x HCl (3.6 g; 10.4 rnmol; from step (i) above) was dissolved in MeOH, pre-saturated with 20 NH3(g), and stirred at room temperature for 3 days. Addition of Et2O (150 rnL) failed to give any preci~ilate. Evaporation of the solvent in vacuo afforded the sub-title compound in a quantitative yield.

LC-MS 286 (M + 1)+

(iii) 3-~2-(4-Amino{t-butoxycarbonylimino~methylphenyl)ethoxy~nitro-benzene 3-~2-(4-Aminoiminomethylphenyl)ethoxy]nitrobenzene x HCl (3.49 g; 10.8 mmol; from step (ii) above) was dissolved in THF (20 mL) and water (10 30 mL). Aqueous NaOH (10 mL; lM; 10 mmol) and di-t-butylcarbonate (2.24 W O 98/01422 ' PCT/SE97/01150 g; 10.3 mmol) were added and the solution stirred at room temperature for 1 hour. THF was removed in vaCuo and the aqueous residue was extracted t~,vice with EtOAc. The combined organic phases were filtered and the solvent evaporated. Purification by flash chromatography (SiO2; CH2Cl2) 5 resulted in partial decomposition of the product. The most pure fractions were combined and recrystallized from CH2C12:Et2O to give 2.02 g (51%) of the sub-title compound.

LC-MS 386 (M + 1)+

(iv) Amino-3-[2-(4-amino{t-butoxycarbonYlimino}methylphenvl)ethoxY]-benzene A suspension of 3-[2-(4-amino{t-butoxycarbonylimino}methylphenyl)-ethoxy]nitrobenzene (1.47 g; 3.81 mmol; from step (iii) above) and Pd 5 (0.236 g; 5% on charcoal) in EtOH (75 mL) was stirred under H2(g) (1 atm.) for 25 minutes. After filtration through Celite the solvent was evaporated.
The residue was purified by preparative HPLC (60% CH3CN/aq:0.1M
NH40Ac) to afford the sub-title compound. Yield: 1.02 g (75%).

20 FAB-MS 356 (M + l)+
'H NMR (300 MHz; CDCI3): ~ 7.80 (d, 2H), 7.35 (d, 2H), 7.05 (t, lH), 6.25-6.35 (m, 2H), 6.20 (t, lH), 4.15 (t, 2H), 3.65 (bs, 2H), 3.12 (t, 2H), 1.55 (s, 9H) 25 (V) N-{3-r2-(4-A minoiminomethylphenyl)ethoxylphenyl~-2-cYanobenzene-sulfonamide x HCI
Prepared using a Vac-Master in accordance with the following procedure.:
Two solutions, one of amino-3-[2-(4-amino{t-butoxycarbonylimino}-methylphenyl)ethoxy]benzene (0.0804M; from step (iv) above) and 4-30 dimethylaminopyridine (0.1046M) in CH3CN, and one of 2-.. . . . ..

cyanophenylsulfonyl chloride (0.124M) in CH3CN were prepared. The solutions (0.700 mL of the first and 0.540 mL of the second) were mixed and left for 6 hours without stirring. The mixture was then filtered through a short plug of silica gel (0.50 g), that was washed with CH3CN (2 x 1 mL).
5 The solvent was removed by a stream of nitrogen gas. The residue was treated with EtOAc, pre-saturated with HCl(g), (3 mL) overnight and the solvent was removed by a stream of nitrogen gas affording the title compound. To estimate the yield, the purity was determined by reversed phase LC (Chromasil C8, 0-100% CH3CN/aq:O.lM NH40Ac) with W-o detection (254 nm). Yield: 48% (LC).

LC-MS 421 (M + 1)+, 419 (M

Example 5 5 N- { 3 - [2-(4-Aminoiminomethylphenyl)ethoxvlphenyl } -2-fluorobenzene-sulfonamide x HCI
Prepared according to the procedure described in Example 4(v) above, using 2-fluorobenzenesulfonyl chloride instead of 2-cyanophenylsulfonyl chloride.
Yield: 80% (LC).

LC-MS 414 (M + 1)+, 412 (M - 1)-Example 6 N- {3-r2-(4-Aminoiminomethylphenyl)ethoxylphenyl~-2-(trifluoromethoxy)-25 benzenesulfonamide x HCl Prepared according to the procedure described in Example 4(v) above, using 2-(trifluoromethoxy)benzenesulfonyl chloride instead of 2-cyanophenyl-sulfonyl chloride. Yield: 80% (LC).

30 LC-MS 480 (M + 1)+, 478 (M - I)~

CA 02260l90 l998-l2-29 Example 7 N- { 3 - ~2-(4-Aminoiminomethylphenyl)ethoxylphenyl } -4-fluorobenzene-sulfonamide x HCI
Prepared according to the procedure described in Example 4(v) above, using 5 4-fluorobenzenesulfonyl chloride instead of 2-cyanophenylsulfonyl chloride.
Yield: ~3% (LC).

LC-MS 414 (M + 1)+, 412 (M - 1)-o Example 8 N- {3-[2-(4-Aminoiminomethylphenyl)ethoxylPhenyl} -2~5-dimethylbenzene-sulfonamide x HCl Prepared according to the procedure described in Example 4(v) above, using 2,5-dimethylbenzenesulfonyl chloride instead of 2-cyanophenylsulfonyl 15 chloride. Yield: 88% (LC).

LC-MS 424 (M + 1)+, 422 (M - 1)-Example 9 20 N- {3-[2-(4-Aminoiminomethylphenyl)ethoxylphenyl}-5-chlorothiophene-2-sulfonamide x HCl Prepared according to the procedure described in Example 4(v) above, using 5-chlorothiophene-2-sulfonyl chloride instead of 2-cyanophenylsulfonyl chloride. Yield: 67% (LC).

LC-MS 436 (M + 1)+, 434 (M - 1)-Example lO
N- {3-r2-(4-AminoiminomethylphenYl)ethoxy~phenyl} - I -methylimidazole-4-sulfonamide x HCI
Prepared according to the procedure described in Example 4(v) above, using 1-methylimidazole-4-sulfonyl chloride instead of 2-cyanophenylsulfonyl chloride. Yield: 44% (LC).

LC-MS 400 (M + 1)+

o Example 11 N- {3-~2-(4-Aminoiminomethylphen~l)ethoxYlphenyl}-3~5-dimethyl-isoxazole-4-sulfonamide x HCl Prepared according to the procedure described in Example 4(v) above, using 3,5-dimethylisoxazole-4-sulfonyl chloride instead of 2-cyanophenylsulfonyl 5 chloride. Yield: 69% (LC).

LC-MS 415 (M + 1)+, 413 (M - 1) Example 12 20 N-{3-~2-(4-Aminoiminomethylphenyl)ethoxylphenyl}benzylsulfonamide x HCI
Prepared according to the procedure described in Example 4(v) above, using benzylsulfonyl chloride instead of 2-cyanophenylsulfonyl chloride. Yield:
71% (LC) LC-MS 410 (M + 1)+, 408 (M - 1)-Example 13 N- {3-[2-(4-Amino iminomethylphenyl)ethoxYlphenyl} -2.5-dichlorothiophene-3-sulfonamide x HCl Prepared according to the procedure described in Example 4(v) above, using 5 2,5-chlorothiophene-3-sulfonyl chloride instead of 2-cyanophenylsulfonyl chloride. Yield: 56% (LC).

LC-MS 471 (M + 1)+

o Example 14 N- {3-[2-(4-Aminoiminomethylphenyl)ethoxy]-5-methylphenyl}-2-chlorobenzenesulfonamide x HOAc The title compound was obtained as a side product from Example 22(iv) below. Yield: 0.014 g (13%).

LC-MS 444 (M + 1)+
IH NM~ (500 MHz; CD30D): ~ 8.03 (dd, lH), 7.75 (d, 2H), 7.50-7.55 (several peaks, 4H), 7.39 (m, lH), 6.52 (t, lH), 6.49 (t, lH), 6.38 (t, lH), 4.13 (t, 2H), 3.13 (t, 2H), 2.55 (t, 2H), 2.18 (s, 3H), 1.93 (s, 3H) Example 15 N- {3-~2-(4-Aminoiminomethylphenyl)ethoxyl-2-methylphenyl}-benzenesulfonamide x CF3COOH

2s (i) 3-t-Butoxycarbonylamino-2-methylphenol 3-Amino-2-methylphenol (2.0 g; 16 mmol) and di-t-butylcarbonate were dissolved in THF (20 mL) and refluxed overnight. Evaporation of the solvent followed by flash chromatography (SiO2; EtOAc 5-30% in isohexane) afforded 2.48 g (69%) of the sub-title compound.

~H NMR (300 MHz; CDCl3): ~ 7.35 (d, lH), 7.02 (t, IH), 6.52 (d, IH), 6.25 (s, lH), 4.86 (s, lH), 2.13 (s, 3H), 1.52 (s, 9H) (ii) t-Butoxycarbonylamino-3-r2-(4-cyanophenYl)ethoxyl-2-meth~lbenzene 5 Triphenylphosphine (1.31 g, 13.5 mmol) and diethylazodicarboxylate (1.7 mL) were dissolved in THF (20 mL) under nitrogen. After 15 minutes 3-t-butoxycarbonylamino-2-methylphenol (2.48 g; 11.1 mmol; from step (i) above) dissolved in THF (20 mL) and 2-(4-cyanophenyl)ethanol (1.9 g, 13 mmol) were added. After 5 days at room temperature water was added and o the stirring continued for 30 minutes. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and the solvent removed in vaCuo. Purification by flash chromatography afforded 2.98 g (77%) of the sub-title compound.

s 'H NMR (300 MHz; CDCl3): ~ 7.4-7.8 (m, SH), 7.10 (m, lH), 6.63 (dd, lH), 6.24 (s, lH), 4.1B (t, 2H), 3.16 (t, 2H), 2.02 (s, 3H), 1.51 (s, 9H) (iii) Amino-3-[2-(4-cyanophenyl)ethoxy]-2-methylbenzene t-Butoxycarbonylarnino-3-[2-(4-cyanophenyl)ethoxy]-2-methylbenzene (2.69 20 g, 7.64 mmol; from step (ii) above) were dissolved in EtOAc, pre-saturated with HCl(g), (150 mL) under nitrogen and stirred at room temperature overnight. After evaporation of the solvent the residue was partitioned between 10% aqueous HCl and EtOAc. The aqueous phase was washed with EtOAc, basified with NaOH (2M, aq.) and extracted with EtOAc. The 25 combined organic phases were washed with brine, dried (MgS04) and the solvent evaporated to afford 0.42 g (19%) of the sub-title compound.

'H NMR (300 MHz; CDCI3): ~ 7.59 (d, 2H), 7.40 (d, 2H), 6.94 (t, lH), 6.31 (dd, 2H), 3.61 (s, 2H), 4.12 (t, 2H), 3.15 (t, 2H), 1.96 (s, 3H) (iv) N- {3-r2-(4-Cyanophenyl)ethoxy]-2-methylphenyl } benzene-sulfonamide Benzenesulfonyl chloride (0.24 mL; 1.9 mmol) was added to a stirred solution of amino-3 -[2-(4-cyanophenyl)ethoxy] -2-methylbenzene (0.42 g; 1. 7 5 mmol; from step (iii) above) in dry pyridine (20 mL) under nitrogen. The reaction was left overnight at room temperature. After evaporation of the solvent the residue was partitioned between 10% aqueous HCI and EtOAc.
The organic layer was washed with brine, dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography afforded 0.47 g 10 (72%) of the sub-title compound.

'H NMR (300 MHz; DMSO-d6): ~ 7.4 - 7.8 (m, 10 H), 7.00 (t, lH), 6.80 (d, lH), 6.50 (d, lH), 4.16 (t, 2H), 3.10 (t, 2H), 1.72 (s, 3H) 15 (V) N- {3-~2-(4-Aminoiminomethylphenvl)-ethoxy]-2-methyl-phenyl} -benzenesulfonamide x CFtCOOH
N- {3-[2-(4-Cyanophenyl)ethoxy]-2-methylphenyl}benzenesulfon~micle (0.47 g; 1.2 mmol; from step (iv) above) was added to a saturated solution of HCl(g) in EtOH (150 mL) and the solution was stirred for 2 days. The 20 solvent was removed by rotary evaporation and the residue treated with EtOH, pre-saturated with NH3(g), for 3 days. After removal of the solvent, the crude product was purified by preparative HPLC (5-95% MeOH:0.1%
trifluoroacetic acid). Recryst~lli7~tion from isopropanol afforded 0.056 g (9%) of the title compound.

LC-MS 410 (M + 1)+
'H NMR (300 MHz; DMSO-d6): ~ 9.55 (bs, lH), 9.25 (bs, 2H), 9.0 (bs, 2H), 7.75 (d, 2H), 7.50-7.70 (several peaks, 7H), 6.99 (t, lH), 6.80 (dd, lH), 6.45 (dd, lH), 4.09 (t, 2H), 3.15 (t, 2H), 1.82 (s, 3H) 30 Analysis calcu}ated for C24H24F3N3O5S: C, 55.06%; H, 4.62%; N, 8.03%; S, ~ , . ... . .

6.12. Found: C, 54.83; H, 4.64%; N, 7.97%; S, 6.12%

Example 16 N- { 5- ~2-(4-Aminoiminomethylphenyl)ethoxyl -2-methylphenyl } benzene-5 sulfonamide x HCl (i) ~2-(4-Cyanophenyl)ethoxYl-4-methyl-3-nitrobenzene 4-Methyl-3-nitrophenol (0.765 g; 5.0 mmol), 2-(4-cyanophenyl)ethanol (0.735 g; 5.0 mmol) and diethylazodicarboxylate (0.87 g; 5.0 mmol) were o dissolved in THF (20 mL). Triphenylphosphine (1.31 g; 5.0 mmol), dissolved in THF (5 mL), was added and the solution stirred overnight.
Evaporation in vacuo and the addition of diethyl ether afforded a yellow solid that was recrystallized from water:acetone (9:1), affording the sub-title compound as yellowish crystals. Yield: 1.04 g (74%).

~H NMR (400 MHz; CDCI3): ~ 7.63 (d, 2H), 7.50 (d, lH), 7.42 (d, 2H), 7.23 (d, lH), 7.04 (dd, lH), 4.14 (t, 2H), 3.09 (t, 2H), 2.53 (s, 3H) (ii) Amino-5-~2-(4-cyanophenyl)ethoxy~-2-methylbenzene 20 Sodium borohydride (0.127 g; 3.35 mmol) was added in portions to a cold suspension (ice:water temperature) of [2-(4-cyanophenyl)ethoxy]-4 methyl 3 nitrobenzene (0.19 g; 0.67 mmol; from step (i) above) and aqueous copper sulfate (1.34 mL; 1 M; 1.34 mmol) in EtOH (5 mL) over five minutes. The temperature was allowed to rise to ambient and the stirring continued for 30 2s minutes. Addition of EtOAc (50 mL) and filtration through Celite afforded a clear solution that was washed with water, dried (K3CO3) and concentrated in vacuo. Flash chromatography (sio2; toluene:EtOAc (10: 1)) afforded 0.044 g (26%) of the sub-title compound as a white solid.

30 IH NMR (400 MHz; CDC13): ~ 7.61 (d, 2H), 7.40 (d, 2H), 6.95 (d, lH), 6.25-6.30 (m, 2H), 4.16 (t, 2H),3.60 (bs, 2H), 3.13 (t, 2H), 2.12 (s, 3H) (iii) N- {5-[2-(4-Cyanophenyl!ethoxyl-2-methylphenyl}benzenesulfonamide Benzenesulfonyl chloride (22 ~L; 0.17 mmol) was added to a cold solution 5 (ice:water temperature) of amino-5-[2-(4-cyanophenyl)ethoxy]-2-methyl-benzene (0.041 g; 0.16 mmol; from step (ii) above) in pyridine (4 mL) The reaction flask was left overnight in a refrigerator. NaHCO3/aq (sat.) was added and the solution extracted twice with EtOAc. The combined organic phases were washed with water, HCl/aq (2M) and water. Drying (MgSO4) o and evaporation of the solvent in vacuo afforded 0.062 g (100%) of the sub-title compound.

lH NMR (500 MHz; CDCl3): ~ 7.78 (d, 2H), 7.66 (d, 2H), 7.59 (t, lH), 7.43-7.50 (m, 4H), 7.02 (d, lH), 6.99 (d, lH), 6.65 (dd, IH), 6.51 (bs, lH), 5 4.18 (t, 2H), 3.17 (t, 2H), 1.91 (s, 3H) (iv) N-{5-~2-(4-Ethoxyiminomethylphenyl)ethoxyl-2-methylphenyl}-benzenesulfonamide x HCI
To a cooled (ice:water temperature) saturated solution of HCl(g) in EtOH (5 20 mL) was added N- { 5- [2-(4-cyanophenyl)ethoxy~-2-methyl-phenyl } benzene-sulfonamide (0.062 g; 0.16 mmol; from step (iii) above). After 30 minutes the temperature was allowed to rise to ambient and the stirring was continued for 20 hours. Evaporation of the solvent afforded the sub-title compound in a quantitative yield. To remove traces of HCI, EtOH was 2s added and evaporated.

LC-MS 439 (M + l)+

(v) N-{5-~2-(4-Aminoiminomethylphenyl)ethoxyl-2-methylphenyl}-benzenesulfonamide x HCI
N- { 5-[2-(4-Ethoxyiminomethylphenyl)ethoxy]-2-methylphenyl } benzene-sulfonamide x HCl (0.076 g; 0.16 mmol; from step (iv) above) was s dissolved in MeOH, pre-saturated with NH3(g), and stirred at room temperature for 20 hours. After evaporation of the solvent in vacuo the residue was redissolved in EtOH and the solvent evaporated to remove HCl(g). Trituration of the residue with methylene chloride afforded 0.045 g (62%) of the title compound.

LC-MS 410 (M + 1)+
'H NMR (400 MHz; CD30D): ~ 7.75 (d, 2H), 7.65 (d, 2H), 7.50-7.60 (m, 3H), 7.45 (t, 2H), 6.95 (d, lH), 6.60-6.70 (m, 2H), 4.09 (t, 2H), 3.13 (t, 2H), 1.85 (s, 3H) Example 17 N-{3-~2-(4-Am inoiminomethylphenyl)ethoxy~-5-methylphenyl}benzene-sulfonamide x HCl 20 (i) t-Butyloxycarbonylamino-3-hydroxy-5-methylbenzene The sub-title compound was prepared according to the method described in Example l(i) above from amino-3-hydroxy-5-methylbenzene (8.0 g; 65 mmol). Yield: 13.2 g (91%).

2s 'H NMR (400 MHz; CDCl3): ~ 6.83 (bs, lH), 6.62 (s, lH), 6.54 (bs, lH), 6.39 (bs, lH), 6.37 (s, lH), 2.22 (s, 3H) 1.50 (s, 9H) (ii) t-Butyloxycarbonylamino-3-~2-(4-cyanophenyl)ethoxy~-5-methylbenzene 30 The sub-title compound was prepared according to the method described in . .

W O g8/01422 PCT/SE97/01150 Example l(ii) above from t-butyloxycarbonylamino-3-hydroxy-5-methyl-benzene(5.9 g; 26.4 mmol; from step (i) above). Yield: 6.21 g (67%).

'H NMR (400 MHz; CDCl3): ~ 7.58 (d, 2H), 7.38 (d, 2H), 6.93 (t, lH), 6.63 (t, lH), 6.44 (bs, lH), 6.37 (t, lH), 4.16 (t, 2H), 3.11 (t, 2H), 2.25 (s, 3H), 1.50 (s, 9H) 3C NMR (100 MHz; CDC13): ~ 159.2, 152.6, 144.3, 140.0, 139.4, 132.2, 129.8, 119.0, 111.8, 110.4, 110.3, 101.9, 80.5, 67.6, 35.9, 28.4, 21.6 o (iii) Amino-3-~2-(4-cyanophenYl)ethoxyl-S-methylbenzene t-Butyloxycarbonylamino-3 - [2-(4-cyanophenyl)ethoxy] - 5 -methylbenzene (1.55 g; 4.4 mmol; from step (ii) above) was stirred in a ~ lule of trifluoroacetic acid (10 mL) and methylene chloride (10 mL) for 3 hours.
The solvent was removed in vacuo. The residue was dissolved in EtOAc (50 15 mL), washed with Na2CO3/aq (sat.) and water, dried (Na2CO3) and the solvent was removed to afford a yellow oil, which crystallized upon standing. Yield: 1.19 g '(100%).

'~I NMR (500 MHz; CDCl3): ~ 7.60 (d, 2H), 7.38 (d, 2H), 6.10-6.15 (m, 20 2H), 6.03 (t, lH), 4.14 (t, 2H), 3.12 (t, 2H), 2.20 (s, 3H) (iv) N-{3-[2-(4-Cyanophenyl)ethoxy]-5-methylphenyl~benzenesulfonamide To a cold solution (ice:water temperature) of amino-[3-2-(4-cyanophenyl)ethoxy]-5-methylbenzene (0.13 g; 0.50 mmol; from step (iii) 25 above) in pyridine (5 mL) was added benzenesulfonyl chloride (71,L~L; 0.55 mmol). After 2 hours stirring, NaHCO3/aq (sat.) was added, and the solution extracted with EtOAc. The combined organic phases were dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (SiO2; EtOAc:heptane (1:1)) to give 0.19 g (97%) of the 30 sub-title compound.

.... . .. .......

WO 98/01422 PCT/SE97/011~0 ~H NMR (500 MHz; CDCl3): ~ 7.82 (d, 2H), 7.62 (d, 2H), 7.5g (t, lH), 7.47 (t, 2H), 7.39 (d, 2H), 6.88 (bs, lH), 6.56 (t, l~I), 6.40-6.45 (m, 2H), 4.15 (t, 2H), 3.14 (t, 2H), 2.22 (s, 3H) s (v) N-{3-~2-(4-Ethoxyiminomethylphenyl)ethoxy]-5-methylphenyl}-benzenesulfonamide x HCI
N- {3-[2-(4-Cyanophenyl)ethoxy]-5-methylphenyl}benzenesulfonamide (0.19 g; 0.50 mmol; from step (iv) above) was added to a cooled (ice:water temperature) saturated solution of HCl(g) in EtOH (S mL). After 30 minutes o the temperature was allowed to rise to ambient temperature and the stirring was continued for 24 hours. Evaporation of the solvent afforded the sub-title compound in a quantitative yield.

lH NM~ (500 MHz; CDCl3): ~ 12.3 (bs, lH), 11.7 (bs, lH), 8.27 (d, 2H), lS 8.02 (bs, lH~, 7.90 (d, 2H), 7.35-7.50 (several peaks, SH), 6.63 (t, lH), 6.57 (t, lH), 6.41 (t, lH), 4.95 (q, 2H), 4.08 (t, 2H), 3.12 (t, 2H), 2.20 (s, 3H), 1.62 (t, 3H) (vi) N-{3-~2-r4-Aminoiminomethylphen~l)ethoxy]-5-methylphenyl}-20 benzenesulfonamide x HCl N- {3-[2-(4-Ethoxyiminomethylphenyl)ethoxy~-S-methylphenyl}benzene-sulfonamide x HCl (0.22 g; 0.50 mmol; from step (v) above) was dissolved in MeOH, saturated with NH3(g), and stirred at room temperature for 24 hours. After evaporation of the solvent in vacuo the residue was redissolved 25 in MeOH (5 mL) and the solution acidified to pH l with EtOH, saturated with HCl(g). The solvent was evaporated and the residue dissolved in MeOH
(S mL). Upon addition of dry Et2O, white crystals precipitated, which were filtered off, affording 0.145 g (65%) of the title compound.

30 LC-MS 410 (M + 1)+

, 'H NMR (500 MHz; CD30D): ~ 9.25 (bs, 2H), 8.75 (bs, 2H), 7.77-7.82 (m, 4H), 7.55-7.61 (m, 3H), 7.48-7.53 (m, 2H), 6.57 (t, lH), 6.45-6.50 (m, 2H), 4.18 (t, 2H), 4.15 (t, 2H), 2.20 (s, 3H) s Example 18 N- {3-[2-(4-Aminoiminomethylphenyl)ethylthiolphenyl}benzenesulfonamide x HCI

(i) 4-Toluenesulfonic acid-2-f4-cyanophenyl)ethyl ester o 2-(4-Cyanophenyl)ethanol (1.46 g; 9.9 mmol) and 4-toluenesulfonyl chloride (1.9 g; 10 mmol) were stirred in pyridine (20 mL) at 5~C for 3 hours. Work-up was performed by removing the solvent, addition of 2M aqueous HCl and extraction with EtOAc. The organic phase was washed with aqueous ci~ic acid, then passed through a short plug of silica gel with Et2O. Removal of 5 the solvent in vacuo afforded a colourless oil, cont~ining ca. 30% of unreacted 2-(4-cyanophenyl)ethanol according to IH NMR. The oil was further subjected to the reaction conditions above for 2 hours. Work-up as above afforded 2.0 g (66%) of the sub-title compound as a yellow solid.

~H NMR (300 MHz; CDCl3): ~ 7.65 (d, 2H), 7.55 (d, 2H), 7.16 (d, 2H), 7.10 (d, 2H), 4.24 (t, 2H), 3.07 (t, 2H), 2.45 (s, 3H) (ii) Amino-3-~2-(4-cyanophenyl)eth~lthiolbenzene 3-Aminothiophenol (0.87 g; 7.0 mmol), 4-toluenesulfonic acid-2-(4-cyano-25 phenyl)ethyl ester (2.0 g; 6.6 mmol; from step (i) above) and K2CO3 (1 g)were stirred in a mixture of EtOH (10 rnL) and CH2Cl2 for 4 hours.
Addition of ether, washing with brine and 2M aqueous NaOH, drying (MgSO4), evaporation of the solvent and flash chromatography (SiO2;
Et2O:hexane (1:1)) afforded 0.82 g (49%) of the sub-title compound.

, . , . , ... .. . _ _ 'H NMR (300 MHz; CDC13): ~ 7.60 (d, 2H), 7.30 (d, 2H), 7.08 (t, lH), 6.75 (dd, lH), 6.71 (t, lH), 6.53 (dd, lH), 3.7 (bs, 2H), 3.13 (t, 2H), 2.96 (t, 2H) (iii) N- {3-r2-(4-Cyanophenvl)ethylthio~phenyl } benzenesulfonamide 5 Benzenesulfonyl chloride (0.62 g; 3.5 mrnol) was added to a cold solution (ice:water temperature) of amino-3-[2-(4-cyanophenyl)ethylthio]benzene (0.80 g; 3.15 mmol; from step (ii) above) in a mixture of pyridine (1 mL) and CH2Cl2 (~0 mL) over 10 minutes. After 3 hours stirring, 2M aqueous HCl was added and the solution extracted with CH2Cl2. The organic layer 10 was dried (MgSO4) and the solvent removed in vaCuo. The residue was purified by flash chromatography (SiO2; Et2O:hexane (1:1)) to give 1.02 g (82%) of the sub-title compound.

LC-MS 395 (M + 1)+, 393 (M - H)-s ~H NMR (300 MHz; CDCl3): ~ 7.80 (d, 2H), 7.60 (d, 2H), 7.4-7.6 (m, 3H), 7.30 (s, lH), 7.0-7.2 (m, 3H), 6.80 (m, 2H), 3.11 (t, 2H), 2.93 (t, 2H) (iv) N-~3-[2-(4-Aminoiminomethylphenyl)ethylthiolphenyl}benzene-sulfonamide x HCl 20 Trimethyl al~-rnin~lm (2.5 mL; 2M in toluene; 5.0 mmol) was added to a cold (ice:water temperature) salul~ted suspension of NH4CI (0.29 g; 5.4 mmol) in toluene. A~ter 30 minutes stirring, N-{3-[2-(4-cyanophenyl)ethyl-thio]phenyl}benzenesulfonamide (1.0 g; 2.6 mmol; from step (iii) above), dissolved in toluene, was added and the mixture was refluxed for 12 hours.
25 The reaction mixture was poured into silica gel (10 g) and CHCI3 (30 mL).
The solids were removed by filtration and washed with methanol. The combined liquid phases were concentrated in vacuo to give a solid residue.
The material was purified twice by preparative HPLC (MeOH:NH4OAc (0.lM aq.)) to obtain the acetate, which was dissolved in MeOH, pre-30 saturated with HCl(g), three times, and evaporated to afford the title .

W 098/01422 PCT/SE97/011~0 compound as a white solid. Yield: 0.63 g (54%).

mp 84-7~C
LC-MS 412 (M + 1)+
s 'H NMR (300 MHz; DMSO-d6): ~ 10.45 (bs, lH), 9.33 (bs, 2H), 9.10 (bs, 2H), 7.75 (m, 4H), 7.0-7.6 (m, 9H), 3.17 (t, 2H), 2.90 (t, 2H) Example 19 N-(2-Chlorophenyl)sulfonyl-3-~2-(4 -aminoiminomethylphenyl)ethoxy]-5-o methylphenylaminoacetic acid ethyl ester x HOAc (i)3-~2-(4-Cyanophenyl!ethoxy~-5-methYlphenylaminoacetic acid ethylester Ethyl bromoacetate (134 ~L, 1.2 mmol) was added to a suspension of amino-3-[2-(4-cyanophenyl)ethoxy]-5-methylbenzene (0.252 g; 1.00 mmol;
s from Example 17(iii) above) and K2CO3 (0.165 g; 1.2 mmol) in DMF (10 mL), and the mixture was stirred for 20 hours. The solvent was removed in ~~acuo and the residue partitioned between water and Et2O. After separation, the aqueous phase was extracted once with Et2O. The combined ether phases were washed with water and brine, dried (MgSO4) and the solvent was 20 removed in vacuo. The residue was purified by flash chromatography (SiO2;
EtOAc:heptane (3:7)) to give 0.30 g (89%) of the sub-title compound, a colourless oil which crystallized upon standing.

~ H NMR (400 MHz; CDCl3): ~ 7.60 (d, 2H), 7.40 (d, 2H), 6.15 (t, lH), 6.08 25 (t, lH), 5.97 (t, lH), 4.25 (q, 2H), 4.16 (t, 2H), 3.95 (s, 2H), 3.14 (t, 2H), 2.23 (s, 3H), 1.30 (t, 3H) (ii) N-~2-Chlorophenyl)sulfonyl-3-r2-(4-cyanophenYl)ethoxyl-S-methYI-phenylaminoacetic acid. ethyl ester 30 2-Chlorobenzenesulfonyl chloride (0.225 g; 1.06 mmol) was added to a cold ., . . , . , ~ . ~, solution (ice:water temperature) of 3-[2-(4-cyanophenyl)ethoxy]-5-methyl-phenylaminoacetic acid, ethyl ester (0.30 g; 0.88 mrnol; from step (i) above) in pyridine (10 mL). After 2 hours stirring the temperature was allowed to rise to ambient. After 4 hours at this temperature more 2-chloro-5 benzenesulfonyl chloride (0.056 g; 0.26 mmol) was added and the mixturewas left overnight. The mixture was then poured into aqueous saturated NaHCO3 and extracted twice with Et2O. The combined ether phases where washed with HCl/aq (2M), H2O and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (SiO2;
EtOAc:heptane (1 :3)) to give 0.28 g (62%) of the sub-title compound.

IH NMR (500 MHz; CDCI3): ~ 7.90 (dd, lH), 7.61 (d, 2H), 7.53 (dd, lH), 7.45 (m, lH), 7.39 (dd, 2H), 7.25 (m, lH), 6.73 (t, lH), 6.62 (t, lH), 6.58 (t, lH), 4.62 (s, 2H), 4.19 (q, 2H), 4.08 (t, 2H), 3.08 (t, 2H), 2.19 (s, 3H), 1.27 (t, 3H) (iii) N-(2-Chlorophenyl)sulfonyl-3-~2-(4-ethoxYiminomethylphenyl)-ethoxyl-5-methylphenylaminoacetic acid ethyl ester x HCl N-(2-Chlorophenyl)sulfonyl-3-[2-(4-cyanophenyl)ethoxy]-5-methylphenyl-20 aminoacetic acid, ethyl ester (0.27 g; 0.53 mmol; from step (ii) above) wasadded to a saturated solution of HCl(g) in EtOH (100 mL) and the solution was stirred for 20 hours. Evaporation of the solvent afforded the sub-title compound in a quantitative yield.

2s LC-MS 559 (M ~ l )+

(iv)N-(2-Chlorophenyl)sulfonyl-3-~2-(4-aminoiminomethylphenyl)ethoxy] -5-methylphenylaminoacetic acid ethyl ester x HOAc N-(2-Chlorophenyl)sulfonyl-3-[2-(4-ethoxyiminomethylphenyl)ethoxy]-5-30 methylphenylaminoacetic acid, ethyl ester x HCl (0.32 g; 0.53 mmol; from step (iii) above) was dissolved in MeOH (pre-saturated with NH3(g)), and stirred at room temperature for 2 days. After evaporation of the solvent in vacuo, the residue was redissolved in EtOH and the solution acidified to pH
1 with EtOH (saturated with HCl(g)). The solvent was evaporated and the 5 residue purified by preparative HPLC (30 - 60% CH3CN:0.lM NH40Ac) to afford 0.03B g (12%) of the title compound.

LC-MS 530 (M + l)+
'H NMR (400 MHz; CD30D): ~ 7.83 (dd, lH), 7.75 (d, 2H), 7.50-7.63 l0 (several peaks, 4H), 7.36 (m, IH), 6.71 (t, lH), 6.60 (m, 2H), 4.62 (s, 2H), 4.17 (q, 2H), 4.12 (t, 2H), 3.12 (t, 2H), 2.16 (s, 3H), 1.90 (s, 3H), 1.22 (t, 3H) Example 20 15 N-(2-Chlorophenyl)sulfonyl-3-[2-(4-aminoiminomethylphenYl)ethoxy]-5-methylphenylaminoacetamide x HOAc The title compound was obtained as a side product in Example 19 above.
Yield: 0.036 g (12%).

20 LC-MS 501 (M + 1)l 'H NMR (400 MHz; CD30D): ~ 7.83 (dd, lH), 7.75 (d, 2H), 7.50-7.63 (several peaks, 4H), 7.34 (m, lH), 6.72 (t, lH), 6.60 (m, 2H), 4.53 (s, 2H), 4.15 (t, 2H), 3.12 (t, 2H), 2.16 (s, 3H), 1.90 (s, 3H) 2s Example 21 N-(2-Chlorophenyl)sulfonyl-3-~2-(4 -aminoiminomethylphenyl)ethoxy~-5-methylphenylaminoacetic acid x HOAc N-(2-Chlorophenyl)sulfonyl-3-~2-(4 -aminoiminomethylphenyl)ethoxy] - 5 -methylphenylaminoacetic acid, ethyl ester x HOAc (0.030 g; 0.050 mmol;
from Example 19 above) was stirred in a mixture of THF (3 mL) and 2M

,, ... .

W 098/01422 PCT/SE97tO1150 5~
LiOH/aq (3 mL) for 4 hours. THF was removed in vaCuo and the resultant suspension was acidified to pH 3 by the addition of HCI/aq (2M). CHICN
was added to dissolve the solid phase. Purification by preparative HPLC
(30% CH3CN:0.lM NH40Ac) afforded 0.011 g (46%) ofthe title compound.

LC-MS 502 (M + 1)+, 500 (M ~
'H NMR (500 MHz; CD30D): ~ 7.86 (dd, lH), 7.75 (d, 2H), 7.58 (d, lH), 7.52 (m, 3H), 7.34 (dt, lH), 6.78 (t, lH), 6.58 (t, lH), 6.53 (t, lH), 4.40 (s, 2H), 4.18 (t, 2H), 3.12 (t, 2H), 2.12 (s, 3H), 1.98 (s, 3H) Example 22 N-(2-Chlorophenyl!sulfonyl-2- {3-~ 2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}propanoic acid. ethyl ester x HOAc s (i) 2-{3-[2-(4-Cyanophenyl)ethoxyl-5-methylphenylamino}propanoic acid~
ethyl ester Amino-3-[2-(4-cyanophenyl)ethoxy]-5-methylbenzene (0.252 g; 1.00 rnmol;
from Example 17(iii) above), ethyl acrylate (130 ~L; 1.2 rnmol) and acetic acid (9 ,uL; 0.15 mmol) were refluxed together for 8 hours. After 20 evaporation in vacuo, the resultant black oil was purifled by flash chromatography (SiO2; EtOAc:heptane (3:7)) to give 0.102 g (29%) of the sub-title compound.

IH NMR (500 MHz; CDCI3): ~ 7.62 (d, 2H), 7.41 (d, 2H), 6.13 (t, lH), 6.10 25 (t, lH), 5.99 (t, lH), 4.15-4.20 (several peaks, 4H), 3.43 (t, 2H), 3.14 (t, 2H), 2.61 (t, 2H), 2.23 (s, 3H), 1.30 (t, 3H) (ii) N-(2-Chlorophenyl)sulfonyl-2- ~3-~2-r4-cyanophenyl)ethoxyl-5 methylphenvlamino}propanoic acid ethyl ester 30 The sub-title compound was prepared according to the method described in , Example l9(ii)abovefrom2-{3-[2-(4-cyanophenyl)ethoxy]-5-methylphenyl-amino}propanoic acid, ethyl ester (0.100 g; 0.28 mmol; from step (i) above) to afford 0.120 g (81%) of a yellowish oil.

s IH NMR (500 MHz; CDCl3): ~ 7.85 (dd, lH), 7.61 (d, 2H), 7.40-7.55 (several peaks, 2H), 7.38 (d, 2H), 7.25 (m, lH), 6.67-6.70 (m, 3H), 4.07-4.15 (several peaks, 6H), 3.10 (t, 2H), 2.58 (t, 2H), 2.20 (s, 3H), 1.22 (t, 3H) o (iii)N-(2-Chlorophenyl)sulfonyl-2- {3-~2-(4-ethoxyiminomethylphenyl)-ethoxyl-5-methylphenylamino}propanoic acid. ethyl ester x HCl The sub-title compound was prepared according to the method described in Example 19(iii) above from N-(2-chlorophenyl)sulfonyl-2-{3-[2-(4-cyano-phenyl)ethoxy]-5-methylphenylamino}propanoic acid, ethyl ester (0.12 g;
s 0.22 mmol; from step (ii) above) to afford 0.13 g (100%) as an oil.

LC-MS 572 (M + 1)+

(iv) N-(2-Chlorophenyl!sulfonyl-2-{3-[2-(4-aminoiminomethylphenyl)-20 ethoxy]-5-methylphenylamino}-propanoic acid. ethyl ester x HOAc The title compound was prepared according to the method described in Example l9(iv) above from N-(2-chlorophenyl)sulfonyl-2-{3-[2-(4-ethoxy-iminomethylphenyl)e~oxy]-5-methylphenylamino}propanoic acid, ethyl ester x HCl (0.13 g; 0.22 mmol; from step (iii) above). Yield: 0.009 g (7%).

LC-MS 543 (M + 1)+
'H NMR (400 MHz; CD30D): ~ 7.70-7.80 (several peaks, 3H), 7.50-7.62 (several peaks, 4H), 7.35 (m, lH), 6.62 (t, lH), 6.55-6.60 (m, 2H), 4.10-4.17 (several peaks, 4H), 4.03 (q, 2H), 3.13 (t, 2H), 2.50 (t, 2H), 2.18 (s, 3H), 1.90 (S, 3H), 1.19 (t, 3H) Example 23 N-(2-Chlorophenyl)sulfonyl-2- {3-~ 2-(4-aminoiminomethylphenyl)ethoxy]-5-methYlphenylamino}propanamide x HOAc The title compound was obtained as a side product in Example 22 above.
5 Yield: 0.0065 g (5%).

LC-MS 514 (M + l)+
IH NMR (400 MHz; CD30D): ~ 7.70-7.80 (several peaks, 3H), 7.50-7.65 (several peaks, 4H), 7.35 (m, lH), 6.62 (t, lH), 6.59 (t, lH), 6.55 (t, lH), o 4.10-4.17 (several peaks, 4H), 3.13 (t, 2H), 2.45 (t, 2H), 2.2 (bs, 2H), 2.18 (s, 3H), 1.92 (s, 3H) Example 24 N-(2-Chlorophenyl)sulfonyl-2- ~3-~ 2-(4-aminoiminomethylphenyl)ethoxy]-5-s methylphenylamino}propanoic acid x HOAc The title compound was prepared according to the method described in Example21 abovefromN-(2-chlorophenyl)sulfonyl-2-~3-[2-(4-aminoimino-methylphenyl)ethoxy]-5-methylphenylamino}propanoic acid, methyl ester x HOAc (0.015 g; 0.025 mmol; from Example 25 below) to afford 0.007 g 20 (48%) of a white solid.

LC-MS 516 (M + l)+
'H NMR (500 MHz; CD30D): ~ 7.85 (d, IH), 7.77 (d, 2H), 7.55-7.62 (several peaks, 4H), 7.35 (m, lH), 6.65 (t, lH), 6.60 (t, lH), 6.53 (t, lH), 2s 4.19 (t, 2H), 4.02 (t, 2H), 3.16 (t, 2H), 2.38 (t, 2H), 2.22 (s, 3H), 1.97 (s, 3H) CA 02260l90 l998-l2-29 Example 25 N-(2-Chlorophenyl)sulfonYI-2-{3-~2-(4-aminoiminomethylphenyl!-ethoxyl 5 methylphenylamino}propanoic acid~ methyl ester x HOAc The title compound was obtained as a side product in Example 22(iv) above.
5 Yield: 0.024 g (19%) LC-MS 530 (M + 1)+
'H NMR (500 MHz; CD30D): ~ 7.75-85 (several peaks, 3H), 7.50-7.65 (several peaks, 4H), 7.37 (m, lH), 6.69 (t, lH), 6.56-6.60 (m, 2H), 4.12-4.20 10 (several peaks, 4H), 3.60 (s, 3H), 3.15 (t, 2H), 2.55 (t, 2H), 2.22 (s, 3H), 1.93 (s, 3H) Example 26 N-(2-Chlorophenyl)sulfonyl-3- {3-[2-(4-aminoiminomethylphenyl)ethoxyl-5-5 methylphenylamino}butanoic acid~ ethYl ester x HOAc (i) 3-~2-~4-Cyanophenyl)ethoxy]-S-methYlphenyl-2-chlorobenzenesulrollalllide 2-Chlorophenylsulfonyl chloride (0.152 g; 0.72 mmol) was added to a cooled solution (ice:water temperature) of amino-3-[2-(4-cyanophenyl)ethoxy]-5-20 methylbenzene (0.16 g; 0.60 mmol; from Example 17(iii) above) inpyridine (5 mL), and the resultant orange solution was stirred for 4 hours. ~ddition of H2O (30 mL), extraction with EtOAc, drying (MgSO4), evaporation of the solvent, and purification by flash chromatography (SiO2; 25-33%
EtOAc:hexane) yielded 0.20 g (78%) of the sub-title compound.

'H NMR (500 MHz; CDCl3): ~ 8.03 (d, lH), 7.61 (d, 2H), 7.45-7.53 (m, 2H), 7.32-7.40 (m, 3H), 7.00 (s, lH), 6.56 (t, lH), 6.47 (t, lH), 6.41 (t, lH), 4.10 (t, 2H), 3.08 (t, 2H), 2.19 (s, 3H) (ii) N-(2-Chlorophenyl!sulfonyl-3- {3-~2-(4-cyanophenvl)ethoxyl-5-methyl-phenylamino}butanoic acid~ ethyl ester Ethyl 3-bromobutanoate (87 ~L; 0.60 mmol) was added to a suspension of 3-[2-(4-cyanophenyl)ethoxy]-5-methylphenyl-2-chlorobenzenesulfonamide 5 (0.171 g; 0.40 mmol; from step (i) above) and K2CO3 (0.166 g; 1.2 mmol) in DMF (10 mL). The mixture was stirred overnight, then poured into water, extracted with Et2O, dried (MgSO4), and the solvent was removed in vacuo.
The residue was purified by flash chromatography (SiO2; EtOAc:hexane (3:7)) to give 0.195 g (90%) of the sub-title compound as a colourless oil.

~H NMR (400 MHz; CDCl3): ~ 7.85 (dd, lH), 7.61 (d, 2H), 7.40-7.52 (several peaks, 2H), 7.38 (d, 2H), 7.25 (m, lH), 6.67-6.70 (m, 3H), 4.07-4.15 (several peaks, 4H), 3.85 (t, 2H), 3.10 (t, 2H), 2.40 (t, 2H), 2.20 (s, 3H), 1.80 (m, 2H), 1.22 (t, 3H) (iii) N-(2-Chlorophenyl)sulfonyl-3-{3-r2-(4-ethoxyiminomethylphenyl)-ethoxyl-5-methylphenylamino}butanoic acid ethyl ester x HCl The sub-title compound was prepared according to the method described i Example l9(iii) above from N-(2-chlorophenyl)sulfonyl-3-{3-[2-(4-cyano-20 phenyl)ethoxy]-5-methylphenylamino}butanoic acid, ethyl ester (0.195 g;
0.36 mmol; from step (ii) above) to afford 0.22 g (100%) of a white foam.

'H NMR (500 MHz; CDCl3): ~ 12.5 (bs, lH), 11.8 (bs, lH), 8.35 (d, 2H), 7.82 (dd, lH), 7.40-7.50 (several peaks, 4H), 7.23 (m, lH), 6.58 (t, lH), 25 6.55 (t, lH), 6.50 (t, lH), 4.95 (q, 2H), 4.02-4.10 (several peaks, 4H), 3.87(t, 2H), 3.10 (t, 2H), 2.40 (t, 2H), 2.20 (s, 3H), 1.80 (m, 2H), 1.60 (t, 3H), 1.22 (t, 3H) (iv) N-(2-ChlorophenYl)sulfonyl-3-{3-~2-(4-aminoiminomethylphenyl)-ethoxy]-5-methylphenylamino}butanoic acid, ethyl ester x HOAc The title compound was prepared according to the method described in Example l9(iv) above from N-(2-chlorophenyl)sulfonyl-3-{3-~2-(4-ethoxy-s iminomethylphenyl)ethoxy]-5-methylphenylamino}butanoic acid, ethyl ester x HCl (0.22 g; 0.36 mmol; from step (iii) above). Yield: 0.063 g (28%).

LC-MS 557 (M + 1~+
'H NMR (400 MHz; CD30D): ~ 7.78 (dd, lH), 7.76 (d, 2H), 7.50-7.60 o (several peaks, 4H), 7.33 (m, lH), 6.63 (t, lH), 6.58 (t, lH), 6.56 (t, lH), 4.15 (t, 2H), 4.07 (q, 2H), 3.87 (t, 2H), 3.13 (t, 2H), 2.41 (t, 2H), 2.18 (s, 3H), 1.90 (s, 3H), 1.74 (m, 2H), 1.21 (t, 3H) Example 27 5 N-(2-Chlorophenyl)sulfonyl-3- {3-r 2-(4-aminoiminome~ylphenyl)ethoxy]-5-methylphenylamino}bllt~n~mide x HOAc NH3(g) was fed into cold MeOH (CO2(s):acetone temperature) until a ca. 1: 1 solution was obtained. The solution was placed in an autoclave with N-(2-chlorophenyl)sulfonyl-3- {3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-20 methylphenylamino}butanoic acid, ethyl ester x HOAc (0.027 g; 0.044rnmol) and NaCN (0.001 g). The closed system was heated to 50~C for 4 days. After cooling, the solvent was removed in vacuo and the residue purified by preparative HPLC (30% CH3CN:0. lM NH40Ac) to afford 0.021 g (81 %) of the title compound.
2s LC-MS 529 (M + l)+
'H NMR (400 MHz; CD30D): ~ 7.70-80 (several peaks, 3H), 7.50-7.60 (several peaks, 4H), 7.33 (m, lH), 6.62 (t, lH), 6.59 (t, lH), 6.55 (t, lH), 4.12 (t, 2H), 3.85 (t, 2H), 3.12 (t, 2H), 2.27 (t, 2H), 2.18 (s, 3H), 1.90 (s, 30 3H), 1.75 (m, 2H) Example 28 N-(2-Chlorophenyl)sulfonYI-3- {3-~ 2-(4-aminoiminomethylphenyl)ethoxy]-5 methylphenylamino}butanoic acid x HCI
The title compound was prepared according to the method described in 5 Example 21 above from N-(2-chlorophenyl)sulfonyl-3- t3-~2-(4-aminoimino-methylphenyl)ethoxy]-5-methylphenylamino} butanoic acid, ethyl ester x HOAc (0.028 g; 0.04S mmol; from Example 26 above). After purification by preparative HPLC, the solid material was dissolved in a small volume of MeOH. HCI/aq (2M) was added and the resultant precipitate was filtered o off, washed with water and dried to afford 0.016 g (63%) of a white solid.

LC-MS 530 (M + 1)+, 528 (M - 1)-'H NMR (400 MHz; CD30D): ~ 7.83 (d, 2H), 7.73 (d, lH), 7.55-7.62 (several peaks, 2H), 7.71 (d, 2H3, 7.33-7.40 (m, lH), 6.62 (t, lH), 6.57 (t, lH), 6.43 (t, lH), 4.10 (t, 2H), 3.83 (t, 2H), 3.08 (t, 2H), 2.20 (t, 2H), 2.18 (s,3H), 1.81 (m,2H) Example 29 N-(2-Chlorophenyl)sulfonyl-4- {3-[2-(4-aminoiminomethylphenyl)ethoxyl-5-20 methylphenylamino}pentanoic acid. ethyl ester x HOAc (i) N-(2-Chlorophenyl)sulfonyl-4-{3-~2-(4-cyanophenyl)ethoxyl-5-methyl-phenylamino}pentananoic acid ethYI ester The sub-title compound was prepared according to the method described in 25 Example 26(ii) above from 3-[2-(4-cyanophenyl)-ethoxy]-5-methylphenyl-2-chlorobenzenesulfonamide (0.171 g; 0.40 mmol; from Example 26(i) above) and ethyl 4-bromopentanoate (95 ,uL; 0.6 mmol). Yield: 0.189 g (85%).

'H NMR (400 MHz; CDCI3): ~ 7.84 (dd, lH), 7.62 (d, 2H), 7.52 (dd, lH), 30 7.42 (m, IH), 7.38 (d, 2H), 7.23 (m, lH), 6.67-6.70 (m, 3H), 4.07-4.15 W O 98/01~22 PCT/SE97/01150 (several peaks, 4H), 3.91 (t, 2H), 3.10 (t, 2H), 2.31 (t, 2H), 2.21 (s, 3H), 1.69 (m, 2H), 1.53 (m, 2H), 1.22 (t, 3H) (ii) N-(2-Chlorophenyl)sulfonyl-4-{3-~2-(4-ethoxyiminomethylphenyl)-5 ethoxyl-5-methylphenYlamino~pentanoic acid ethyl ester x HCI
The sub-title compound was prepared according to the method described Example l9(iii) above from N-(2-chlorophenyl)sulfonyl-4-{3-[2-(4-cyano-phenyl)ethoxy]-5-methylphenylamino}pentanoic acid, ethyl ester (0.189 g, 0.34 mmol; from step (i) above) in a quantitative yield.

~H NMR (500 MHz; CDCl3): ~ 12.5 (bs, lH), 11.8 (bs, lH), 8.35 (d, 2H), 7.82 (dd, lH), 7.40-7.50 (several peaks, 4H), 7.23 (m, lH), 6.58 (t, lH), 6.55 (t, lH), 6.50 (t, lH), 4.95 (q, 2H), 4.02-4.10 (several peaks, 4H), 3.89 (t, 2H), 3.10 (t, 2H), 2.30 (t, 2H), 2.20 (s, 3H), 1.70 (m, 2H), 1.62 (t, 3H), s 1.53 (m, 2H), 1.22 (t, 3H) (iii) N-(2-Chlorophenyl)sulfonyl-4-{3-[2-(4-aminoiminomethylphenYI)-ethoxyJ-5-methylphenylamino~pentanoic acid ethyl ester x HOAc The title compound was ~repar~d according to the method described 20 Example l 9(iv) above from N-(2-chlorophenyl)sulfonyl-4- {3-[2-(4-ethoxy-iminomethylphenyl)ethoxy]-5-methylphenylamino}pentanoic acid, ethyl ester x HCI (0.22 g; 0.34 mmol; from step (ii) above). Yield: 0.070 g (33%).

LC-MS 572 (M + 1)+
25 IH NMR (400 MHz; CD30D): ~ 7.79 (dd, lH), 7.76 (d, 2H), 7.50-7.60 (several peaks, 4H), 7.33 (m, lH), 6.62 (t, lH), 6.58 (m, 2H), 4.15 (t, 2H), 4.05 (q, 2H), 3.83 (t, 2H), 3.13 (t, 2H), 2.30 (t, 2H), 2.18 (s, 3H), 1.90 (s, 3H), 1.67 (m, 2H), 1.48 (m, 2H), 1.19 (t, 3H) . . ~

Example 30 4- {3-~2-(4-Aminoiminomethylphe nYl)ethoxyl-N-(2-chlorophen-~l)sulfonyl-5-methylphenylamino}pentanamide x HOAc The title compound was prepared according to the method described in 5 Example 27above from N-(2-chlorophenyl)sulfonyl-4- {3-[2-(4-aminoimino-methylphenyl)ethoxy]-5-methylphenylamino}pentanoic acid, ethyl ester x HOAc (0.022 g; 0.035 mmol; from Example 29 above). Yield: 0.009 g (42%).

o LC-MS 543 (M + 1)+
'H NMR (400 MHz; CD30D): ~ 7.79 (dd, lH), 7.76 (d, 2H), 7.50-7.60 (several peaks, 4H), 7.32 (m, lH), 6.62 (t, lH), 6.58 (t, lH), 6.55 (t, lH), 4.13 (t, 2H), 3.82 (t, 2H), 3.12 (t, 2H), 2.19 (t, 2H), 2.18 (s, 3H), 1.90 (s, 3H), 1.67 (m, 2H), 1.48 (m, 2H) Example 31 N-(2-Chlorophenyl)sulfonyl-4- {3-~ 2-(4-aminoiminomethylphenyl)ethoxyl-5-methylphenylamino}pentanoic acid x HCl The title compound was prepared according to the method described 20 Example28abovefromN-(2-chlorophenyl)sulfonyl-4-{3-[2-(4-aminoimino-methylphenyl)ethoxy]-5-methylphenylamino}pentanoic acid, ethyl ester x HOAc (0.026 g; 0.041 mmol; from Example 29 above). Yield: 0.016 g (46%).

25 LC-MS 544 (M + 1)+
'H NMR (400 MHz; CD30D): ~ 7.90 (d, 2H), 7.74 (dd, lH), 7.50-7.60 (several peaks, 4H), 7.40 (m, lH), 6.63 (t, lH), 6.58 (t, lH), 6.43 (t, lH), 4.12 (t, 2H), 3.82 (t, 2H), 3.12 (t, 2H), 2.33 (t, 2H), 2.20 (s, 3H), 1.75 (m, 2H), 1.48 (m, 2H) Example 32 N-(2-ChlorophenYl)sulfonyl-S-~3-[2-(4-aminoiminomethylphenyl)ethoxyl S
methylphenylamino~hexanoic acid~ ethyl ester x HOAc 5 (i) N-(2-Chlorophenyl)sulfonyl-5-{3-~2-(4-cyanophenYl)ethoxy~-s-met phenylamino}hexanoic acid. ethyl ester The sub-title compound was pl~aled according to the method described in Example 26(ii) above from 3-[2-(4-cyanophenyl)ethoxy]-5-methylphenyl-2-chlorobenzenesulfonamide (0.150 g; 0.35 mmol; from Example 26(i) above) o and ethyl S-bromohexanoate (75 ~L; 0.42 mmol). Yield: 0.185 g (93%).

~H NMR (400 MHz; CDCI3): ~ 7.83 (dd, lH), 7.61 (d, 2H), 7.50 (dd, lH), 7.42 (m, lH), 7.38 (d, 2H), 7.26 (m, lH), 6.67-6.70 (m, 3H), 4.07-4.15 (several peaks, 4H), 3.78 (t, 2H), 3.10 (t, 2H), 2.27 (t, 2H), 2.20 (s, 3H), 1.59 (m, 2H), 1.50 (m, 2H), 1.38 (m, 2H), 1.25 (t, 3H).

(ii) N-(2-Chlorophenyl)sulfonyl-S-t3-[2-(4-ethoxYiminomethylphenyl)-ethoxyl-5-methylphenylamino}hexanoic acid. ethyl ester x HCI
The sub-title compound was prepared according to the method described 20 Example l 9(iii) above from N-(2-chlorophenyl)sulfonyl-S- {3-[2-(4-cyano-phenyl)ethoxy]-5-methylphenylamino}hexanoic acid, ethyl ester (0.185 g;
0.32 mmol) from step (i) above in a quantitative yield.

lH NMR (500 MHz; CDCI3): ~ 12.5 (bs, lH), 11.8 (bs, lH), 8.35 (d, 2H), 2s 7.80 (dd, lH), 7.40-7.50 (several peaks, 4H), 7.23 (m, lH), 6.58 (t, lH), 6.55 (t, IH), 6.48 (t, lH), 4.92 (q, 2H), 4.00-4.10 (several peaks, 4H), 3.79 (t, 2H), 3.10 (t, 2H), 2.22 (t, 2H), 2.19 (s, 3H), 1.70 (m, 2H), 1.52-1.60 (several peaks, 5H), 1.48 (m, 2H), 1.35 (m, 2H), 1.21 (t, 3H) (iii) N-(2-Chlorophenyl)sulfonyl-5-{3-~2-(4-aminoiminomethylphenyl)-ethoxy]-5-methylphenylamino}hexanoic acid~ ethyl ester x HOAc The title compound was prepared according to the method described in Example l9(iv) above from N-(2-chlorophenyl)sulfonyl-5-{3-[2-(4-ethoxy-5 iminomethylphenyl)ethoxy]-5-methyphenylamino} hexanoic acid, ethyl ester x HCI (0.21 g, 0.34 mmol; from step (ii) above). Yield: 0.11 g (74%).

LC-MS 586 (M + l)+
H NMR (500 MHz; CD30D): ~ 7.79 (dd, lH), 7.76 (d, 2H), 7.50-7.60 o (several peaks, 4H), 7.35 (m, lH), 6.62 (t, lH), 6.58 (m, 2H), 4.16 (t, 2H), 4.10 (q, 2H), 3.83 (t, 2H), 3.15 (t, 2H), 2.28 (t, 2H), 2.19 (s, 3H), 1.90 (s, 3H), 1.58 (m, 2H), 1.47 (m, 2H), 1.40 (m, 2H), 1.22 (t, 3H) 15 Example 33 N-(2-Chlorophenyl)sulfonyl-5- {3-~2-(4-aminoiminomethylphenyl)ethoxyl-5-methylphenylamino}hexanamide x HOAc The title compound was prepared according to the method described in Example27abovefromN-(2-chlorophenyl)sulfonyl-5-{3-[2-(4-aminoimino-20 methylphenyl)ethoxy~-5-methylphenylamino}hexanoic acid, ethyl ester x HOAc (0.020 g; 0.031 mmol; from Example 32 above). Yield: 0.010 g (52%).

LC-MS 557 (M + l)+
'H NMR (400 MHz; CD30D): ~ 7.79 (dd, lH), 7.76 (d, 2H), 7.50-7.60 (several peaks, 4H), 7.32 (m, lH), 6.62 (t, lH), 6.58 (t, lH), 6.55 (t, lH), 4.13 (t, 2H), 3.81 (t, 2H), 3.12 (t, 2H), 2.19 (2, 3H), 2.17 (t, 2H), 1.90 (s, 3H), 1.56 (m, 2H), 1.46 (m, 2H), 1.39 (m, 2H) Example 34 N-(2-Chlorophenyl)sulfonyl-5- {3-~ 2-(4-aminoiminomethylphenyl)ethoxyl 5 methylphenylamino}hexanoic acid x HOAc The title compound was prepared according to the method described in 5 Example 21 above fromN-(2-chlorophenyl)sulfonyl-5- {3-[2-(4-aminoimino-methylphenyl)ethoxy]-5-methylphenylamino}hexanoic acid, ethyl ester x HOAc (0.040 g; 0.062 mmol) from Example 32 above. Yield: 0.026 g (68%).

o ESI-MS 558 (M + 1)+, 556 (M - 1)-'H NMR (400 MHz; CD30D): ~ 7.82 (dd, lH), 7.78 (d, 2H), 7.50-7.60 (several peaks, 4H), 7.35 (m, lH), 6.62 (t, lH), 6.57 (t, lH), 6.52 (t, lH), 4.12 (t, 2H), 3.81 (t, 2H), 3.12 (t, 2H), 2.19 (s, 3H), 1.90 (s, 3H), 1.56 (m, 2H), 1.46 (m, 2H), 1.39 (m, 2H) Example 35 N-Phen~lsulfonyl-3-[2-(4-aminoiminomethylphenyl)ethoxy]phenylamino-acetic acid~ ethyl ester x HOAc 20 (i) N-Phenylsulfonyl-3-r2-(4-cyanophenyl)ethoxylPhenylaminoacetic acid~
ethyl ester N-{3-[2-(4-Cyanophenyl)ethoxy]phenyl}benzenesulfonamide (0.179 g; 0.47 mmol; from Example l(iv) above), K2CO3 (0.082 g; 0.59 mmol) and ethyl bromoacetate (63 ,uL; 0.57 mmol) were stirred in DMF (10 rnL) for 1 hour 25 at room temperature, then 1 hour at 60~C. The mixture was filtered and the solvent removed in vacuo. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted with EtOAc. The combined organic portions were dried (Na2SO4) and the solvent evaporated to afford the sub-title compound in a quantitative yield.

.

FAB-MS 465 (M + 1)+

(ii) N-(2-Phenyl)sulfonYl-3-[2-(4-aminoiminomethylphenyl)ethoxy]phen aminoacetic acid ethyl ester x HOAc s Prepared according to the method described Example l(v) and l(vi) above from N-(2-chlorophenyl)sulfonyl-3-[2-(4-cyanophenyl)ethoxy]phenyl-aminoacetic acid, ethyl ester (0.225 g, 0.47 mmol; from step (i) above), which resulted only in a ca. 50% conversion ('H NMR). The material was thus subjected, without further purification, to the reaction conditions as o described in Example l(vi) above. Purification by ~lcpa~ative HPLC (50%
CH3CN:0.lM NH40Ac/aq)) afforded the title compound. The overall yield was 0.060 g (24%).

FAB-MS 482 (M + l)+
IH NMR (300 MHz; CD30D): ~ 7.76 (d, 2H), 7.50-7.70 (several peaks, 7H), 7.15 (m, lH), 6.80-6.90 (several peaks, 2H), 6.63 (t, lH), 4.40 (s, 2H), 4.05-4.20 (several peaks, 4H), 3.15 (t, 2H), 1.90 (s, 3H), 1.21 (t, 3H) Example 36 20 N-Phenylsulfonyl-3-~2-(4-aminoiminomethylphenyl)ethoxylPhenylaminO-acetic acid x HCI
Aqueous NaOH (1.6 mL; lM, 0.16 mmol) was added to a solution of N-phenylsulfonyl-3- [2-(4-aminoiminomethylphenyl)ethoxy]phenylaminoacetic acid, ethyl ester x HOAc (0.041 g, 0.079 mmol; from Example 35 above) in MeOH (3 mL) and the mixture was stirred overnight. Aqueous lM HCI
was added and the resultant precipitate was filtered off and dried, affording 0.016 g (41%) of the title compound.

LC-MS 454 (M + 1)+, 452 (M ~ ; FAB-MS 454 (M + 1)+
IH NMR (400 MHz; CD30D): ~ 7.73 (d, 2H), 7.55-7.65 (several peaks, 3H), 7.42-7.55 (several peaks, 4H), 7.08 (t, lH), 6.82 (t, lH), 6.75 (dd, lH), 6.63 (dd, lH), 4.20 (t, 2H), 4.17 (s, 2H), 3.15 (t, 2H) Example 37 5 N- {3-~2-(4-Aminoiminomethylphenyl)ethoxylphenyl}-N-(2-hydroxyethyl)-benzenesulfonamide x HOAc (i) N- {3-~2-(4-Cyanophenyl)ethoxy~phenyl~-N-(2-hydroxyethyl)-benzene-sulfonamide o N- {3-[2-(4-cyanophenyl)ethoxy]phenyl}benzenesulfonamide (0.093 g; 0.246 mmol; from Example l(iv) above), K2CO3 (0.047 g, 0.34 mmol), 2-chloroethanol (0.028 g; 0.34 mmol) and NaI (0.052 g; 0.34 mrnol) were stirred in DMF (4 mL) for 24 hours at 100~C. The solvent was removed in vacuo. The residue was dissolved in water and extracted twice with EtOAc.
5 The combined organic portions were washed with brine, dried (Na2SO4) and the solvent evaporated. Purification by flash chromatography (SiO2;
toluene:EtOAc 10:0, 9:1, 8:2, 6:4) afforded 0.047 g (45%) of the sub-title compound.

IH NMR (300 MHz; CDCl3): ~ 7.55-7.65 (several peaks, 4H), 7.40 (d, 2H), 7.15-7.30 (several peaks, 4H), 6.83 (dd, lH), 6.73 (t, lH), 6.55 (dd, lH), 4.15 (t, 2H), 3.67 (m, 4H), 3.15 (t, 2H) (ii) N- {3-~2-(4-Amino(hydroxyimino)methylphenyl)ethoxylphenyl}-N-(2-25 hydroxyethyl)-benzenesulfonamide N- { 3 - [2-(4-Cyanophenyl)ethoxy]phenyl } -N-(2-hydroxyethyl)-benzene-sulfonamide (0.046 g, 0.108 mmol; from step (i) above), hydroxylamine hydrochloride (0.010 g, 0.15 mmol) and triethylamine (26 ,uL, 0.18 mmol) were heated to reflux for 5 hours. Evaporation in vaCuo and flash 30 chromatography afforded 0.033 g (67%) of the sub-title compound.

FAB-MS 456 (M + l)+

(iii) N- ~3-[2-(4-Aminoiminomethylphenyl)ethoxylphenyl}-N-(2-hydroxy-ethyl!-benzenesulfonamide x HOAc 5 A suspension of N-{3-[2-(4-amino(hydroxyimino)methylphenyl)ethoxy]-phenyl}-N-(2-hydroxyethyl)-benzenesulfonamide (0.033 g, 0.072 mmol;
from step (ii) above), Pd (0.011 g; 10% on charcoal), HOAc (21 ,uL; 0.36 mmol), in EtOH (10 mL) and water (0.5 mL) was stirred under an atmosphere of H2(g) for 6 hours. After filtration through Celite, the solvent o was removed in vacuo and the residue was purified by preparative HPLC
(50% CH3CN:0.lM NH40Ac/aq) to afford the title compound. Yield: 0.010 g (28%).

LC-MS 440 (M + l)+
s ~H NMR (300 MHz; D20): ~ 7.45-7.80 (several peaks, 9H), 7.30 (t, lH), 6.97 (dd, lH), 6.80 (dd, lH), 6.55 (t, lH), 4.22 (t, 2H), 3.72 (t, 2H), 3.55 (t, 2H), 3.13 (t, 2H), 1.98 (s, 3H) 3C NMR (75 MHz; D2O): ~ 167.2, 159.1, 146.2, 139.8, 136.8, 134.5, 130.9, 130.5, 130.0, 128.5, 128.1, 126.6, 122.9, 116.7, 116.0, 69.2, 59.2, 53.5, 35.2 Example 38 N- {3-[2-(4-Aminoiminomethylphenyl)ethoxy]phen~/l}-N-(dimethyloxo-phosphinylmethyl)-benzenesulfonamide x HOAc 25 (i) N- { 3 -~2-(4-Cyanophenyl)ethoxylphenyl } -N-(dimethyloxophosphinyl-methyl)-benzenesulfonamide N- {3-[2-(4-Cyanophenyl)ethoxy]phenyl}benzenesulfonamide (0.224 g; 0.59 mmol; from Example l(iv) above), K2CO3 (0.111 g; 0.803 mmol) and chloromethyl dimethylphosphinoxide (0.090 g; 0.711 mmol) were stirred in 30 DMF (10 mL) at 60~C for 8 hours, 3 days at room temperature, and then 24 hours at 60~C. NaI (0.11 g; 0.73 mmol) was subsequently added and the mixture was heated to 100~C for 1 day. The solvent was removed in vacuo and the residue dissolved in water. Extraction with EtOAc, drying (Na2SO4), evaporation in vaC~o and purification by flash chromatography (SiO2;
s toluene:EtOAc) afforded 0.125 g (45%) of the sub-title compound.

FAB-MS 469 (M + 1)+
IH NMR (400 MHz; CDCl3): ~ 7.58-7.63 (several peaks, 3H), 7.52 (d, 2H), 7.45 (t, 2H), 7.38 (d, 2H), 7.18 (t, lH), 6.82 (dd, IH), 6.68 (t, lH), 6.55 o (dd, lH), 4.11 (t, 2H), 3.96 (d, 2H), 3.12 (t, 2H), 1.46 (d, 6H) (ii) N-{3-[2-(4-Amino(hvdroxyimino)methylphenyl)ethoxYlphenyl}-N-(dimethyloxophosphinylmeth~ -benzenesulfonamide Hydroxylamine hydrochloride (0.018 g; 0.26 mmol) and triethylamine (45 15 ~L, 0.33 mmol) were added to a solution of N-{3-[2-(4-cyanophenyl)-ethoxy]phenyl} -N-(dimethyloxophosphinylmethyl)-benzenesulfonamide (0.090 g; 0.192 mmol; from step (i) above) in EtOH (6 mL). The mixture was heated at reflux for 3 hours, stirred at room temperature overnight and then refluxed for 1 hour. Evaporation of the solvent in vacuo and flash 20 chromatography (SiO2; EtOAc:MeOH (9:1)) afforded 0.054 g (56%) of the sub-title compound.

lH NMR (400 MHz; CDCl3): ~ 7.58-7.64 (several peaks, 3H), 7.53 (dd, 2H), 7.46 (t, 2H), 7.27 (d, 2H), 7.19 (t, lH), 6.84 (ddd, lH), 6.56-6.61 (m, 2H), 25 4.9 (bs, 2H), 4.10 (t, 2H), 3.95 (d, 2H), 3.08 (t, 2H), 1.45 (d, 6H) (iii) N-{3-~2-(4-Aminoiminomethylphenyl)ethoxylphenyl~-N-(dimethyl-oxophosphinylmethyl)-benzenesulfonamide x HOAc The title compound was ~ure~aled according to the method described in 30 Example 37(iii) abovefromN- {3-[2-(4-amino(hydroxyimino)methylphenyl) CA 02260190 l998-l2-29 ethoxy]phenyl} -N-(dimethyloxophosphinylmethyl)-benzenesulfonamide (0.012 g; 0.024 mmol; ~rom step (ii) above). Yield: 0.009 g (69%).

'H NMR (300 MHz; D2O): ~ 7.70-7.80 (several peaks, 3H), 7.47-7.62 (several peaks, 6H), 7.30 (t, lH), 6.97 (dd, lH), 6.83 (dd, 2H), 6.65 (t, lH), 4.1-4.3 (several peaks, 4H), 3.13 (t, 2H), 1.90 (s, 3H), 1.52 (d, 6H) 13C NMR (100 MHz; D20): ~ 177.8, 166.5, 158.6, 145.7, 139.9, 134.9, 134.4, 130.6, 130.0, 129.5, 127.9, 127.8, 125.9, 121.8, 116.4, 115.1, 68.6, 50.2 (d), 34.7, 21.2, 13.7 (d) Example 39 2-Chlorobenzenesulfonic acid~ 3-[2-(4-aminoiminomethylphenyl)ethoxyl-5-methylphenyl ester x HOAc 15 (i) 3-~2-(4-Cyanophenyl)ethoxyl-5-methylphenol Triphenylphoshine (7.86 g; 30 mmol), 3,5-dihydroxytoluene (2.5 g; 20 mmol) and 2-(4-cyanophenyl)ethanol (4.41 g; 30 mmol) were dissolved in THF (50 mL). Diethylazodicarboxylate (5.22 g; 30 mmol; dissolved in THF
(10 mL)), was added and the solution was stirred at room temperature 20 overnight. The solvent was removed in vacuo and the white solid residue extracted with Et2O. Purification by flash chromatography (SiO2;
toluene:EtOAc (10:1)) afforded 1.85 g (37%) of the sub-title compound as a white solid.

25 EC-MS 252 (M ~
~H NMR (500 MHz; CDCl3): ~ 7.60 (d, 2H), 7.39 (d, 2H), 6.28 (t, lH), 6.26 (t, lH), 6.20 (t, lH), 4.95 (bs, lH), 4.17 (t, 2H), 3.13 (t, 2H), 2.25 (s, 3H) (ii) 3-[2-(4-Amino(hydroxYimino)methylphenvl)ethoxy]-5-methylphenol x HCI
3-[2-(4-Cyanophenyl)ethoxy]-5-methylphenol (0 39 g; l .54 mmol; from step (i) above), hydroxylamine hydrochloride (0.128 g; 1.85 mmol) and 5 triethylamine (281 ~4L; 2.00 mmol) were dissolved in EtOH (4 mL) and stirred at 80~C for 20 minutes, then at room temperature overnight. The solvent was removed by evaporation and the residue was partitioned between dilute HCl/aq (pH 3) and CH2Cl2. The aqueous phase was washed with CH2CI2 and stored in a refri~elatol for 3 days. The precipitate which was o obtained was filtered off and washed with Et2O, yielding 0.33 g (75%) of the sub-title compound.

LC-MS 287 (M + l)+
'H NMR (400 MHz; CD30D): ~ 7.63 (d, 2H), 7.55 (d, 2H), 6.19 (m, 2H), 5 6.10 (t, lH), 4.16 (t, 2H), 3.14 (t, 2H), 2.18 (s, 3H) (iii) 3-~2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenol x HOAc The sub-title compound was prepared using the method described in Example 37(iii) above from 3-[2-(4-amino(hydroxyimino)methylphenyl)-20 ethoxy]-5-methylphenol x HCI (0.27 g; 0.94 mmol; from step (ii) above).
Yield: 0.265 g (85%).

LC-MS 271 (M + 1)+
'H NMR (400 MHz; CD30D): ~ 7.78 (d, 2H), 7.53 (d, 2H), 6.21 (t, lH), 2s 6.18 (t, lH), 6.13 (t, lH), 4.13 (t, 2H), 3.11 (t, 2H), 2.18 (s, 3H), 2.0 (bs, 3H) (iv) 3-~2-(4-amino{t-butoxycarbonylimino~methylphenyl)ethoxy~-5-methylphenol 30 Di-t-butylcarbonate (1.38 g; 6.3 mmol) was added to a suspension of 3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenol x HCI (1.9 g; 6.0 mmol; from step (iii) above) and NaHCO3 (1.51 g; 18 mmol) in THF (50 mL) and water (20 mL). After stirring overnight at room temperature, more di-t-butylcarbonate (0.263 g; 1.2 mmol) was added and the stirring continued 5 for 6 hours. THF was removed in vaCuo and the aqueous residue was extracted with MeOH:CH2Cl2 (1:4). The combined organic phases were washed with brine, dried (MgS04) and the solvent was evaporated.
Purification by flash chromatography (SiO2; EtOAc:hexane (1:2, 1:1)) afforded 1.8 g (81%) of the sub-title compound.

LC-MS 371 (M + 1)+, 369 (M - 1)-'H NMR (500 MHz; CD30D): ~ 7.76 (d, 2H), 7.41 (d, 2H), 6.21 (m, 2H), 6.14 (t, lH), 4.14 (t, 2H), 3.10 (t, 2H), 2.20 (s, 3H), 1.52 (s, 9H) 5 (V) 2-Chlorobenzenesulfonic acid. 3-~2-(4-amino{t-butoxycarbonylimino~-methylphenyl)ethox~l-5-methylphenyl ester To a solution of 3-[2-(4-amino{t-butoxycarbonylimino}methylphenyl)-ethoxy]-5-methylphenol (0.025 g; 67.5 mmol; from step (iv) above) and 4-dimethylaminopyridine (0.011 g; 88 mmol) in CH3CN (5 mL) was added 2-20 chlorobenzenesulfonyl chloride (0.023 g; 81 mmol). The mixture was stirredat room temperature for one day, then filtered through a short plug of silica gel. After removal of the solvent in vacuo the residue was purif1ed by flash chromatography (SiO2; CH2Cl2:MeOH (1:0, 98:2)) yielding 0.018 g (49%) of the sub-title compound.

'H NMR (500 MHz; CD30D): ~ 7.89 (dd, lH), 7.75 (d, 2H), 7.70 (m, lH), 7.66 (tt, lH), 7.44 (dt, lH), 7.35 (d, 2H), 6.62 (t, lH), 6.46 (t, lH), 6.38 (t,lH), 4.07 (t, 2H), 3.04 (t, 2H), 2.19 (s, 3H), 1.51 (s, 9H) W O 98/01422 PCT/SE97/011~0 (vi) 2-Chlorobenzenesulfonic acid~ 3-~2-(4-aminoiminomethylphenyl)ethoxyl 5-methylphenyl ester x HOAc 2-Chlorobenzenesulfonic acid, 3-[2-(4-amino {t-butoxycarbonylimino} -methylphenyl)ethoxy]-s-methylphenyl ester (0 015 g; 0.028 mmol; from step 5 (V) above) was added to EtOAc, presaturated with HCl(g), (3 mL) and the mixture was stirred at room temperature overnight. Evaporation of the solvent and purification by p.epalali~e HPLC (50% CH3CH:0. lM
NH40Ac/aq) afforded the title compound Yield: 0.010 g (80%).

o LC-MS 444 (M f l)+
'H NMR (500 MHz; CD30D): ~ 7.90 (dd, lH), 7.66-7.76 (several peaks, 4H), 7.52 (d, 2H), 7.45 (dt, lH), 6.63 (t, lH), 6.46 (t, lH), 6.42 (t, lH), 4.13 (t, 2H), 3.13 (t, 2H), 2.19 (s, 3H), 1.90 (s, 3H) 5 Example 40 Benzenesulfonicacid 3-~2-(4-aminoiminomethylphenyl)ethoxylphenyl ester x HOAc (i) Benzenesulfonic acid. 3-hYdroxyphenyl ester 20 The sub-title compound was prepared according to the method described in Example 2(i) above from 1,3-dihydroxybenzene (4.50 g; 40.9 mmol). Yield:
5.1 g (50%)-LC-MS 249 (M - 1)-(ii) Benzenesulfonic acid. 3-r2-(4-cyanophenyl)ethoxylphenyl ester The sub-title compound was plepar~d according to the method described in Example 2(ii) above from benzenesulfonic acid, 3-hydroxyphenyl ester (3.57 g; 14.3 mmol; from step (i) above). Yield: 3.7 g (69%).

~H NMR (400 MHz; CDCI3): ~ 7.85 (dd, 2H), 7.66 (tt, lH), 7.61 (d, 2H), 7.52 (t, 2H), 7.36 (d, 2H), 7.13 (t, lH), 6.75 (dd, lH), 6.60 (t, lH), 6.50 (dd, lH), 4.11 (t, 2H), 3.11 (t, 2H) (iii) Benzenesulfonic acid. 3-~2-(4-amino{hydroxyimino}methylphenyl) ethoxy~phenyl ester The sub-title compound was prepared using the method described in Example 38(ii) above from benzenesulfonic acid, 3-[2-(4-cyanophenyl)-ethoxy~phenyl ester (0.100 g; 0.264 mmol; from step (ii) above). Yield:
0.095 g (88%).

LC-MS 413 (M + 1)+

(iv) Benzenesulfonic acid. 3-~2-(4-aminoiminomethylphenyl)ethoxylphenyl 15 ester x HOAc The title compound was l~lc~ared according to the method described in Example 37 (iii) from benzenesulfonic acid,3-[2-(4-amino{hydroxyimino}-methylphenyl)ethoxy]phenyl ester (0.085 g; 0.21 mmol; from step (iii) above). Yield: 0.021 g (25%).

LC-MS 397 (M + 1)+
IH NMR (400 MHz; CDCI3): ~ 7.81 (m, 2H), 7.75 (d, 2H), 7.73 (tt, lH), 7.58 (m, 2H), 7.53 (d, 2H), 7.16 (t, lH), 6.80 (ddd, lH), 6.53 (t, lH), 6.50 (ddd, lH), 4.15 (t, 2H), 3.14 (t? 2H), 1.89 (s, 3H) Example 41 2-Chloro-4-fluorobenzenesulfonic acid~ 3-[2-(4-aminoiminomethylphenyl)-ethoxy~-S-chlorophenyl ester x HOAc 5 (i) Chloro-3.5-dihydroxybenzene BBr3 (26 rnL; 0.275 mmol) was added to a solution of chloro-3,5-dimethyoxybenzene (10 g; 30 mmol) in CH2Cl2 (100 mL) at -70~C. The cooling bath was removed and the solution was stirred at room temperature for 4 days. After re-cooling to -70~C, MeOH was added (150 mL). After o evaporation of the solvent, toluene was added and removed in vacuo.
Purification by kugelrohr distillation afforded 9 g (100%) of the sub-title compound.

'H NMR (300 MHz; CD30D): ~ 6.30 (d, 2H), 6.18 (t, lH), 4.9 (bs, lH) (ii) 3-Chloro-5-[2-(4-cyanophenyl)ethoxylPhenol Triphenylphoshine (32 g; 122 mmol) and diethylazodicarboxylate (19.2 rnL;
122 rnrnol) were dissolved in CH2Cl2 (150 mL). Chloro-3,5-dihydroxybenzene (9.1 g; 63 mmol; from step (i) above) and 2-(4-20 cyanophenyl)ethanol (9.04 g; 61 mmol) were added and the solution wasstirred at room temperature overnight. The mi~lule was diluted with Et2O
and filtered through Celite. The solvent was removed in vacuo. Purification, first by flash chromatography (SiO2; CH2Cl2:MeOH), then by preparative HPLC (60% CH3CN:0. 1 M NH40Ac/aq), afforded 3.55 g (21%) of the sub-25 title compound.

~H NMR (300 MHz; CDCl3): ~ 7.60 (d, 2H), 7.40 (d, 2H), 6.45-50 (m, 2H), 6.27 (t, lH), 5.5 (bs, lH), 4.15 (t, 2H), 3.12 (t, 2H) .

(iii) 2-Chloro-4-fluorobenzenesulfonic acid~ 3-~2-(4-cyanophenyl)ethox~-5-chlorophenyl ester 2-Chloro-4-fluorobenzenesulfonyl chloride (1.16 g; 5.0 mmol) was added to a cold solution (ice:water temperature) of 3-chloro-5-[2-(4-cyanophenyl) ethoxy]phenol (0.689 g; 2.5 mmol; from step (ii) above) in pyridine (8 mL).
The temperature was allowed to rise (slowly) to ambient overnight. The mixture was re-cooled (ice:water temperature) and ice was added to the reaction flask. After stirring for 4 hours, the pyridine was removed in vacuo.
CH2Cl2 was then added and the organic layer was washed with aqueous o KHSO4 and water. Drying (MgSO4), evaporation of the solvent and purification by flash chromatography (SiO2; CH2Cl2) afforded 0.84 g (72%) of the sub-title compound.

~H NMR (300 MHz; CDCl3): ~ 7.97 (m, lH), 7.60 (d, 2H), 7.30-7.40 5 (several peaks, 3H), 7.12 (m, lH), 6.80 (t, lH), 6.72 (t, lH), 6.63 (t, lH), 4.14 (t, 2H), 3.12 (t, 2H) (iv) 2-Chloro-4-fluorobenzenesul~onic acid 3-~2-(4-ethoxyiminomethyl-phenyl)ethoxy]-5-chlorophenyl ester x HCI
20 The sub-title compound was prepared according to the method described Example l9(iii) above from 2-chloro-4-fluorobenzenesulfonic acid, 3-[2-(4-cyanophenyl)ethoxy]-5-chlorophenyl ester(0.576 g; 1.2 m~nol; from step (iii) above) in a quantitative yield.

2s 'H NMR (400 MHz; CD30D): ~ 7.97-8.03 (several peaks, 3H), 7.63 (dd, lH), 7.57 (d, 2H), 7.28 (m, lH), 6.89 (t, lH), 6.70 (t, lH), 6.60 (t, lH), 4.62 (q, 2H), 4.22 (t, 2H), 3.18 (t, 2H), 1.61 (t, 3H) (v) 2-Chloro-4-fluorobenzenesulfonic acid 3-[2-(4-aminoiminomethyl-phenyl)ethoxy]-S-chlorophenyl ester x HOAc The title compound was prepared according to the method described in Example l9(iv) above from 2-chloro-4-fluorobenzenesulfonic acid, 3-[2-(4-ethoxyiminomethylphenyl)ethoxy]-5-chlorophenyl ester x HCl (0.718 g; 1.3 mmol; from step (iv) above). Yield: 0.097 g (15%).

LC-MS 483 (M + 1)+
'H NMR (400 MHz; CD30D): ~ 8.01 (m, lH), 7.74 (d, 2H), 7.63 (dd, lH), o 7.53 (d, 2H), 7.28 (m, lH), 6.89 (t, lH), 6.70 (t, lH), 6.61 (t, lH), 4.20 (t, 2H), 3.16 (t, 2H), 1.88 (s, 3H) Example 42 2-Chlorobenzenesulfonic acid.3-~2-(4-aminoiminomethylphenyl)ethoxy~-5-s methoxyphenyl ester x HCI

(i) 2-Chlorobenzenesulfonic acid~ 3-hydroxy-5-methoxyphenyl ester Triethylamine (1.4 g; 14 mmol) was added to a solution of 3,5-dihydroxymethoxybenzene (2.0 g; 14 mmol) and 2-chlorobenzenesulfonyl 20 chloride (3.3 g; 15.7 mmol) in pyridine (50 mL), and the mixture was stirred at room tel~pelature overnight. Filtration through silica and purification by preparative HPLC afforded 0.998 g (22%) of the sub-title compound.

~H NMR (500 MHz; CDCl3): ~ 7.97 (dd, lH), 7.55-7.62 (m, 2H), 7.38 (dt, lH), 6.27 (m, 3H), 5.4 (bs, lH), 3.68 (s, 3H) (ii) 2-Chlorobenzenesulfonic acid.3-[2-(4-cyanophenyl)ethoxyl-s-meth phenyl ester The sub-title compound was prepared using the method described in 30 Example 1 (ii) above from 2-chlorobenzenesulfonic acid, 3-hydroxy-5-methoxyphenyl ester (0.80 g; 2.5 rnmol; from step (i) above). Purification by preparative HPLC afforded 0.50 g (45%) of the sub-title compound.

'H NMR (400 MHz; CDC13): ~ 7.97 (dd, lH), 7.55-7.62 (several peaks, 4H), 5 7.38 (dt, lH), 7.35 (d, 2H), 6.32 (t, lH), 6.28 (t, lH), 6.25 (t, lH), 4.08 (t, 2H), 3.68 (s, 3H), 3.08 (t, 2H) ~iii) 2-Ch~orobenzenesulfonic acid~ 3-~2-(4-ethoxyiminomethylphenyl)-ethoxy~-5-methoxyphenyl ester x HCl o The sub-title compound was ~lel~ared using the method deseribed in Example 3(iv) above from 2-chlorobenzenesulfonic acid and 3-[2-(4-cyanophenyl)ethoxy]-S-methoxyphenyl ester (0.50 g; 1.1 mrnol; from step (ii) above) yielding 0.48 g (87%) of the sub-title compound.

5 LC-MS 490 (M + 1)+

(iv) 2-Chlorobenzenesulfonic acid. 3-[2-(4-aminoiminomethylphenyl)ethoxy~-S-methoxyphenyl ester x HCl The title compound was ~ a~ed using the method described in Example 20 3(v) above from 2-chlorobenzenesulfonic acid,3-[2-(4-ethoxyiminophenyl)-ethoxy]-5-methoxyphenyl ester x HCl (0.48 g; 0.98 mmol; from step (iii) above). Freeze-drying with 1 molar equivalent of HCl afforded 0.39 g (80%) of the title compound.

25 LC-MS 461 (M + 1)+
'H NMR (500 MHz; CD30D): ~ 7.92 (dd, lH), 7.63-7.76 (several peaks, 4H), 7.52 (d, 2H), 7.47 (m, lH), 6.34 (t, lH), 6.24 (t, lH), 6.19 (t, lH), 4.14 (t, 2H), 3.69 (s, 3H), 3.13 (t, 2H) _, ... .. ...........

Example 43 2-Chlorobenzenesulfonic acid 3-~2-(4-aminoiminomethylphenyl)ethoxyl-5-ethylphenyl ester x HOAc (i) Ethyl-3 5-dimethoxybenzene The sub-title compound was prepared according to the procedure described in J. Chem. Soc. 859 (1949) from 3,5-dimethoxyacetophenone (5.0 g; 28 mmol). Yield 3.41 g (74%).

o ~H NMR (400 MHz; CD30D): ~ 7.23 (m, 2H), 7.18 (t, lH), 3.72 (s, 3H), 2.50 (q, 2H), 1.18 (t, 3H) (ii) Ethyl-3 5-dihydroxybenzene The sub-title compound was prepared according to the procedure described 5 in J. Chem. Soc. 859 (1949) from ethyl-3,5-dimethoxybenzene (3.5 g; 21 mmol; from step (i) above). Yield 2.85 g (98%).

LC-MS 139 (M - 1)-'H NMR (400 MHz; CD30D): ~ 7.14 (m, 2H), 7.08 (t, lH), 2.46 (q, 2H),20 1.17 (t, 3H) (iii) 3-~2-(4-Cyanophenyl!ethoxYl-S-ethylphenol The sub-title compound was ~lepaled using the method described in Example 39(i) above from ethyl-3,5-dihydroxybenzene (1.2 g; 8.69 mmol;
2s from step (ii) above). Yield: 0.182 g (7.8%).

LC-MS 266 (M - 1) ~H NMR (400 MHz; CDC13): ~ 7.62 (d, 2H), 7.41 (d, 2H), 6.33 (t, lH), 6.30 (t, lH), 6.20 (t, lH), 4.75 (bs, lH), 4.17 (t, 2H), 3.15 (t, 2H), 2.57 (q, 2H), 1.22 (t, 3H) (iv) 2-Chlorobenzenesulfonic acid. 3-[2-(4-ethoxyiminomethylphenyl)-ethoxyl-5-ethvlphenyl ester x HCI
3-[2-(4-Cyanophenyl)ethoxy]-5-ethylphenol (0.040 g; 0.15 mmol; from step (iii) above) and triethylamine (0.018 g; 0.18 mmol) were dissolved in CH2Cl2 and 2-chlorobenzenesulfonyl chloride (0.050 g; 0.18 mmol) was added. After stilTing for 2 hours, the mixture was washed with saturated K2CO3/aq and NaCI/aq. Filtration through a short plug of silica gel and evaporation of the solvent afforded 0.064 g of a solid. The solid material was stirred in EtOH (presaturated with HCl) overnight. Removal of excess o HCl and the solvent in vacuo afforded 0.076 g (97%) of the sub-title compound.

LC-MS 488 (M + l)+

15 (v)2-Chlorobenzenesulfonicacid~3-~2-~4-aminoiminomethYIphenyl)ethoxv~-5-ethylphenyl ester x HOAc 2-Chlorobenzenesulfonic acid, 3 - [2-(4-ethoxyiminomethylphenyl)ethoxy]-5-ethylphenyl ester x HCl (0.076 g; 0.15 mmol; from step (iv) above) was stiIred in MeOH, presaturated with NH3(s), (20 mL) for 1 day at room 20 temperature. After evaporation in vacuo, the residue was purified by ion exchange chromatography to obtain the free amidine, which was freeze-dried from aqueous HOAc yielding 0.015 g (22%) of the title compound.

LC-MS 459 (M + 1)+

Example 44 N- { 2 - [2 -(4-Aminoiminomet hylphenyl)ethylthio]phenyl } -benzenesulfonamide x HCI

5 (i) Amino-2-~2-(4-cyanophenyl)ethylthio]benzene 4-Toluenesulfonic acid,2-(4-cyanophenyl)ethyl ester (1.9 g; 6.3 mmol; from Example 18(i) above) and K2CO3 (2.0 g) were added to a solution of 2-aminothiophenol (0.875 g; 7.0 mmol) in EtOH (20 rnL). The ~ luie was heated to reflux for 48 hours, cooled, filtered and concentrated in vacuo to o an oil which was dissolved in EtOAc (50 mL) and washed with water (25 mL). The organic portion was dried (MgSO4) and concentrated. The residue was purified by flash chromatography (SiO2; Et2O:hexane (1:1)) to obtain 1.32 g (78%) of the sub-title product as a viscous oil.

~H NMR (300 MHz; CDCl3): ~ 7.57 (dd, 2H), 7.36 (dd, 2H), 7.26 (d, 2H), 7.14 (dt, lH), 6.67-6.75 (m, 2H), 4.30 (bs, 2H), 3.05-3.10 (m, 2H), 2.95-3.05 (m, 2H) (ii) N- {2- ~2-(4-Aminoiminomethylphenyl)ethylthio]phenyl } -benzene-20 sulfonamide x HCl Benzenesulfonyl chloride (1.0 g; 5.7 mmol) was added dropwise over 10 minutes to a solution of amino-2-[2-(4-cyanophenyl)ethylthio]benzene (1.30 g; 5.11 mmol; from step (i) above) in a mixture of pyridine (2 mL) and CH2Cl2 (10 mL). After 2 hours stirring at room tempcl~Lule the solution 25 was diluted with CH2C12 (25 mL) and washed with aqueous 2M citric acid (25 mL). The organic portion was dried (MgSO4) and the solvent removed in vacuo. The residue was filtered through a short column of silica with diethylether to afford a colourless oil (1.41 g). This oil was dissolved in a saturated solution of HCI in EtOH (30 mL) and maintained at room 30 temperature for 48 hours. The solvent was removed in vacuo and the brown ,, . ~ , W 0 98/01422 PCT/SE97/OllSO

residue was dissolved in 7M methanolic ammonia. After a further 24 hours the solvent was evaporated and the product was purified by preparative HPLC (MeOH:CF3COOH/aq (0.lM)) to obtain the trifluoroacetate, which was dissolved three times in MeOH, presaturated with HCl(g), and 5 evaporated, to afford the title compound as a white solid. Yield: 0.63 g (28%).

mp 78-83~C
LC-MS 412 (M + 1)+
o 'H NMR (300 MHz; CDC13): ~ 9.60 (bs, lH), 9.38 (s, 2H), 9.16 (s, 2H), 7.70-7.80 (m, 4H), 7.60-7.70 (m, 3H), 7.52 (d, 2H), 7.40 (dd, 2H), 7.22 (dt, 2H), 7.18 (dt, lH), 6.94 (dd, lH), 3.08 (t, 2H), 2.85 (t, 2H) Example 45 15 N-{2-~2-(4-Aminoiminomethylphenyl)ethylthiolphenyl3-2~4~5-trichloro-benzenesulfonamide x CF3COOH

(i) Amino-2-[2-(4-aminoiminomethylphenyl)ethylthiolbenzene Amino-2-[2-(4-cyanophenyl)ethylthio]benzene (0.670 g; 2.63 mrnol) from 20 Example 44(i) above was dissolved in EtOH (presaturated with HCl; 2.5 mL), and stirred for 2 days. The solvent was evaporated, the residue was dissolved in toluene (50 mL) and concentrated in vacuo. The residue was dissolved in 7M methanolic ammonia at 0~C and stirred overnight. The solvent was evaporated and crude product purified by preparative HPLC to 25 afford the sub-title compound. Yield: 0.47 g (66%).

mp 228-30~C
LC-MS 272 (M + H)+
'H NMR (300 MHz; DMSO-d6): ~ 9.42 (s, 2H), 7.80 (d, 2H), 7.4-7.5 (m, 30 3H), 7.2-7.3 (m, 2H), 7.12 (t, lH), 3.23 (t, 2H), 2.95 (t, 2H) (ii)N-{2-~2-(4-Aminoiminomethylphenyl)ethylthiolphenyl}-2~4 5-trichloro-benzenesulfonamide x CF3COOH
Amino-2-[2-(4-aminoiminomethylphenyl)ethylthio]benzene (from step (i) above) was attached to a Wang resin (0.7 mmol functional groups (benzyl 5 alcohol)/g) that had been modified with 4-nitrophenyl chloroformate as follows: Wang resin (0.100 g; 0.7 mmol/g; 0.07 mmol) was added to a solution of amino-2-[2-(4-aminoiminomethylphenyl)ethylthio]benzene (0.054 g; 0.20 mmol) in N-methylpyrrolidone (2 mL). Triethylamine (0.100 mL) was added and the mixture was gently stirred overnight at room 10 temperature. The Wang resin was filtered off and washed five times with CH2Cl2.

The resin was then sul~onated and deprotected as follows: The resin (0.004 g; 0.7 mmol/g; 0.0028 mmol) was swelled with CH2Cl2 (0.100 mL) and a 15 solution of 2,6-lutidine in CH2Cl2 (0.040 mL; 1.0 mol/L; 0.040 mmol) was added. A solution of 2,4,5-trichlorobenzenesulfonyl chloride (0.020 mL; 0.25 mol/L; 0.0050 mmol) was then added and the resultant mixture was shaken at room temperature overnight. More 2,4,5-trichlorobenzenesulfonyl chloride (0.040 mL; 0.25 mol/L; 0.010 mmol) was added and the reaction continued 20 for 3 days. The resin was filtered off and washed five times with CH2Cl2.
The title compound was cleaved off using a 20% solution of trifluoroacetic acid in CH2C12 (2 x 5 mL) and the solvents were removed in a vacuum desiccator. To estimate the yield, the purity was determined by LC-MS to 89%.

LC-MS: 516 (M + H)+, 514 (M - 1)-Example 46 N- {2-[2-(4-Aminoiminomethylphenyl)eth~llthio~phenyl}-2-chloro-5-methoxYbenzenesulfonamide x CF3COOH
The title compound was prepared according to the procedure described in Example 45 above, using 2-chloro-5-methoxyphenylsulfonyl chloride instead o~ 2,4,5-trichlorobenzenesulfonyl chloride. Yield: 87% (LC).

LC-MS: 476 (M + H)+, 474 (M - 1)-10 Example 47 N- {2- [2-(4-Aminoiminomethylphenyl)ethYlthio]phenyl } -2.5-dibromo-benzenesulfonamide x CF3COOH
The title compound was prepared according to the procedure described in Example 45 above, using 2,5-dibromophenylsulfonyl chloride instead of s 2,4,5-trichlorobenzenesulfonyl chloride. Yield: 81% (LC).

LC-MS: 570 (M + 1)+, 568 (M - 1)-Example 48 20 N-{2-~2-(4-Aminoiminomethylphenyl)ethylthiolphenyl}-2 5-dichloro-benzenesulfonamide x CF3COOH
The title compound was ple~aled according to the procedure described inExample 45 above, using 2,5-dichlorophenylsulfonyl chloride instead of 2,4,5-trichlorobenzenesulfonyl chloride. Yield: 69% (LC).
2s LC-MS: 480 (M + H)+, 478 (M - 1)-Example 49 N- {2- ~2-f4-Aminoiminomethylphenyl)-ethylthiol-phenyl~ -2-methox~-5-methylbenzenesulfonamide x CF3COOH
The title compound was prepared according to the procedure described in 5 Example 45 above, using 2-methoxy-5-methylphenylsulfonyl chloride instead of 2,4,5-trichlorobenzenesulfonyl chloride. ~ield: 84% (LC).

LC-MS: 456 (M + H)+

o Example 50 N- {2-[2-(4-Aminoiminomethylphenyl)ethylthio]phenYl} -2~3 ~5~6-tetramethylbenzenesulfonamide x CF3COOH
The title compound was prepared according to the procedure described in Example 45 above, using 2,3,5,6-tetramethylphenylsulfonyl chloride instead ~s of 2,4,5-trichlorobenzenesulfonyl chloride. Yield: 84% (LC).

LC-MS: 468 (M + H)+, 466 (M - 1)-Example 51 20 N-{2-~2-(4-A minoiminom ethylphenyl)ethYlthio]phenyl}-3~4-dimethox~-benzenesulfonamide x CF3COOH
The title compound was prepared according to the procedure described inExample 45 above, using 3,4-dimethoxyphenylsulfonyl chloride instead of 2,4,5-trichlorobenzenesulfonyl chloride. Yield: 88% (LC).

LC-MS: 472 (M + H)+, 470 (M - 1)-, Example 52 N- {2-[2-(4-AminoiminomethYlphenyl)ethylthio]phenyl}-3-bromo-benzenesulfonamide x CF3COOH
The title compound was prepared according to the procedure described in 5 Example 45 above, using 3-bromophenylsulfonyl chloride instead of 2,4,5-trichlorobenzenesulfonyl chloride. Yield: 80% (LC).

LC-MS: 490 (M + H)+, 4~8 (M - 1)-o Example 53 N- {2-r2-~4-Aminoiminomethylphenyl)eth~lthiolphenyl~-3~4-dibromobenzene-sulfonamide x CF3COOH
The title compound was prepared according to the procedure described in Example 45 above, using 3,4-dibromophenylsulfonyl chloride instead of 5 2,4,5-trichlorobenzenesulfonyl chloride. Yield: 75% (LC).

LC-MS: 570 (M + H)+, 568 (M - 1)-Example 54 20 N- ~2-[2-(4-Aminoiminomethylphenyl)ethylthiolphenyl}-2-chloro-4-fluorobenzenesulfonamide x CF3COOH
The title compound was p~e~aled according to the procedure described in Example 45 above, using 2-chloro-4-fluorophenylsulfonyl chloride instead of 2,4,5-trichlorobenzenesulfonyl chloride. Yield: 100% (LC).

LC-MS: 465 (M + H)+, 463 (M - I) Example 55 N- {2- ~2-(4-Aminoiminomethylphenyl)ethylthiolphenyl } -5-bromo-2-methoxybenzenesulfonamide x CF3COOH
The title compound was prepared according to the procedure described in s Example 45 above, using 5-bromo-2-methoxyphenylsulfonyl chloride instead of 2,4,5-trichlorobenzenesulfonyl chloride. Yield: 85% (LC).

LC-MS: 520 (M + H)+

o Example 56 The title compounds of Examples 1 to 55 were tested in Test A andlor B
and/or Test C above and were found to exhibit an IC50 value and/or a K
value (as a~ro~liate) of less than 0.3 ~M.

s Abbreviations Ac= acyl DCC= dicyclohexylcarbodiimide DMF= dimethylformamide 20 EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et= ethyl Et2O = diethyl ether EtOAc = ethyl acetate EtOH= ethanol 2s h= hours HCl(g) = hydrogen chloride gas HPLC = high performance liquid chromatography HOAc = acetic acid HOBt= N-hydroxybenzotriazole 30 LC = liquid chromatography , ... . ...

Me= methyl MeOH= methanol THF= tetrahydrofuran s Prefixes n, s, i and t have their usual me~ning~: normal, iso, secondary and tertiary.

Claims (34)

Claims

1. A compound of formula I, wherein one of R1 and R2 represents a structural fragment of formula Ia and the other represents R4;
Z represents O or N(R5);
R3 represents one or more optional substituents selected from OH, halo, cyano, nitro, C(O)OR6, C1-6alkoxy or C1-6 alkyl (which two latter groups are optionally substituted and/or terminated by one or more halo or hydroxy group) or N(R7)R8;
R4 represents H, OH, halo, cyano, nitro, C(O)OR6, C1-6 alkoxy or C1-6 alkyl (which two latter groups are optionally substituted and/or terminated by one or more halo or hydroxy group) or N(R7)R8;
Ar1 represents phenyl, C1-3 alkylphenyl, C1-3 alkyldiphenyl, C3-7 cycloalkyl, C1-3-alkyl-C3-7-cycloalkyl, C1-3-alkyl-di-C3-7-cycloalkyl, naphthyl, C1-3 alkylnaphthyl, thienyl, imidazolyl or isoxazolyl, all of which may be substituted by one or more substituent selected from OH, halo, cyano, nitro, C(O)OR6, C1-6 alkoxy or C1-6 alkyl (which two latter groups are optionally substituted and/or terminated by one or more halo or hydroxy group) or N(R7)R8;
R5 represents H, C1-6 alkyl, phenyl or C1-3 alkylphenyl (which three latter groups are optionally substituted and/or terminated by one or more substituent selected from OH, halo, cyano, nitro, C(O)OR9, C(O)N(R10)R11, P(O)(R12)R13, P(O)(OR14)OR15, S(O)2(R16)R17, S(O)2N(R18)R19, C1-6 alkoxy or C1-6 alkyl (which two latter groups are optionally substituted and/or terminated by one or more halo or hydroxy group) or N(R20)R21);
Y represents O, S, S(O), S(O)2 or N(R22);
R10 and R11 independently represent H, OR23, C(O)R24, OC(O)R25, C(O)OR26, C1-4 alkyl, (which latter group is optionally substituted and/or terminated by one or more substituent selected from C1-4 alkyl, OR27, N(R28)R29, C(O)OR30 C(O)N(R31)R32, P(O)(R33)R34, P(O)(OR35)OR36 and S(O)2N(R37)R38), -(CH2CH2O-)p R39 or, together with the nitrogen atom to which they are attached, form a C4-7 nitrogen-containing, aromatic or non-aromatic, ring which ring may contain a further heteroatom or group (as appropriate) selected from O, S and N(R40) and may further be substituted by one or more substituent selected from C(O)R41, C(O)OR42 or C(O)N(R43)R44;
R28, R29, R30, R31, R32 and R40 independently represent H or C1-6 alkyl, which latter group is optionally substituted and/or terminated by one or more substituent selected from C(O)R45, C(O)OR46 or C(O)N(R47)R48;
at each occurance, R6, R7 and R8 independently represent H or C1-4 alkyl;
R9, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R33, R34, R35, R36, R37, R38, R39, R41, R42, R43, R44, R45, R46, R47 and R48 independently represent H or C1-4 alkyl;
n represents 0, 1, 2, 3 or 4;
p represents 1, 2, 3, 4, 5 or 6; and B represents a structural fragment of formula Ib, Ic, Id or Ie wherein X1 and X2 independently represent a single bond or CH2;
or a pharmaceutically acceptable salt thereof.

2. A compound of formula I, as defined in Claim 1, wherein, when B
represents a structural fragment of formula Ib, Id, Ie or Ic in which latter fragment X1 and X2 both represent CH2, then n represents 2.

3. A compound of formula I, as defined in one Claim 1, wherein n represents 2.

4. A compound of formula I, as defined in any one of the preceding claims, wherein R2 represents a structural fragment of formula Ia and R1 represents R4.

5. A compound of formula I, as defined in any one of the preceding claims, wherein Z represents O or N(R5), in which latter case R5 represents C1-6 alkyl terminated by C(O)N(R10)R11.

6. A compound of formula I, as defined in any one of the preceding claims, wherein R3 is not present, or represents methyl, chloro or methoxy.

7. A compound of formula I, as defined in any one of the preceding claims, wherein Ar1 represents substituted phenyl.

8. A compound of formula I, as defined in any one of the preceding claims wherein Y represents O.

9. A compound of formula I, as defined in any one of the preceding claims wherein B represents a structural fragment of formula Ib.

10. A compound as claimed in Claim 1 which is:
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}benzenesulfonamide;
benzenesulfonic acid-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methyl}phenyl ester;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-2-chlorobenzenesulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-2-cyanobenzene-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-2-fluorobenzene-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-2-(trifluoromethoxy)-benzenesulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-4-fluorobenzene-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-2,5-dimethylbenzene-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-5-chlorothiophene-2-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-1-methylimidazole-3-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-3,5-dimethylisoxazole-4-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}benzylsulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-2,5-dichlorothiophene-3-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenyl}-2-chlorobenzenesulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-2-methylphenyl}-benzenesulfonamide;
N-{5-[2-(4-aminoiminomethylphenyl)ethoxy]-2-methylphenyl}benzene-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenyl}benzene-sulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}benzenesulfonamide;
N-(2-chlorophenyl)sulfonyl-3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylaminoacetic acid, ethyl ester;
N-(2-chlorophenyl)sulfonyl-3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylaminoacetamide;
N-(2-chlorophenyl)sulfonyl-3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylaminoacetic acid;
N-(2-chlorophenyl)sulfonyl-2-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}propanoic acid, ethyl ester;
2-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-N-(2-chlorophenyl)sulfonyl-5-methylphenylamino}propanamide;
N-(2-chlorophenyl)sulfonyl-2-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}propanoic acid;
N-(2-chlorophenyl)sulfonyl-2-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}propanoic acid, methyl ester;
N-(2-chlorophenyl)sulfonyl-3-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}butanoic acid, ethyl ester;
3-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-N-(2-chlorophenyl)sulfonyl-5-methylphenylamino}butanamide;
N-(2-chlorophenyl)sulfonyl-3-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}butanoic acid;
N-(2-chlorophenyl)sulfonyl-4-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}pentanoic acid, ethyl ester;
4-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-N-(2-chlorophenyl)sulfonyl-5-methylphenylamino}pentanamide;
N-(2-chlorophenyl)sulfonyl-4-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}pentanoic acid;
N-(2-chlorophenyl)sulfonyl-5-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}hexanoic acid, ethyl ester;
5-{3-[2-(4-aminoiminomethylphenyl)ethoxy]- N-(2-chlorophenyl)sulfonyl-5-methylphenylamino}pentanamide;
N-(2-chlorophenyl)sulfonyl-5-{3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenylamino}hexanoic acid;
N-phenylsulfonyl-3-[2-(4-aminoiminomethylphenyl)ethoxy]phenylamino-acetic acid, ethyl ester;
N-phenylsulfonyl-3-[2-(4-aminoiminomethylphenyl)ethoxy]phenylamino-acetic acid;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-N-(2-hydroxyethyl)-benzenesulfonamide;
N-{3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl}-N-(dimethyloxo-phosphinylmethyl)-benzenesulfonamide;
2-chlorobenzenesulfonic acid, 3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methylphenyl ester;
benzenesulfonic acid, 3-[2-(4-aminoiminomethylphenyl)ethoxy]phenyl ester;
2-chloro-4-fluorobenzenesulfonic acid, 3-[2-(4-aminoiminomethylphenyl)-ethoxy]-5-chlorophenyl ester;
2-chlorobenzenesulfonic acid, 3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-methoxyphenyl ester;

2-chlorobenzenesulfonic acid, 3-[2-(4-aminoiminomethylphenyl)ethoxy]-5-ethylphenyl ester;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}benzenesulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-2,4,5-trichloro-benzenesulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-2-chloro-5-methoxybenzenesulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-2,5-dibromo-benzenesulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-2,5-dichloro-benzenesulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)-ethylthio]-phenyl}-2-methoxy-5-methylbenzenesulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-2,3,5,6-tetramethylbenzenesulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-3,4-dimethoxy-benzenesulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-3-bromo-benzenesulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-3,4-dibromobenzene-sulfonamide;
N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-2-chloro-4-fluorobenzenesulfonamide; or N-{2-[2-(4-aminoiminomethylphenyl)ethylthio]phenyl}-5-bromo-2-methoxybenzenesulfonamide.

11. A compound of formula I, as defined in Claim 1, provided that R1 represents a structural fragment of formula Ia and R2 represents R4.

12. A compound of formula I, as defined in Claim 1, provided that Ar1 represents optionally substituted phenyl.

13. A compound of formula I, as defined in Claim 1, provided that R5 is not substituted by P(O)(OR14)OR15, S(O)2(R16)R17 or S(O)2N(R18)R19.

14. A compound of formula I, as defined in Claim 1, provided that R10 and/or R11 represent H or unsubstituted C1-4 alkyl.

15. A compound of formula I, as defined in Claim 1, provided that Y
represents O, S or N(R5).

16. A compound of formula I, as defined in Claim 1, provided that B
represents a structural fragment of formula Ib, Ic or Id.

17. A compound of formula I, as defined in Claim 1, provided that R2 represents a structural fragment of formula Ia and R1 represents R4.

18. A compound of formula I, as defined in Claim 1, provided that Ar1 does not represent optionally substituted phenyl.

19. A compound of formula I, as defined in Claim 1, provided that R5 is substituted by P(O)(OR14)OR15, S(O)2(R16)R17 or S(O)2N(R18)R19.

20. A compound of formula I, as defined in Claim 1, provided that R10 and/or R11 do not represent H or unsubstituted C14 alkyl.

21. A compound of formula I, as defined in Claim 1, provided that Y
represents S(O) or S(O)2.

22. A compound of formula I, as defined in Claim 1, provided that B

represents a structural fragment of formula Ie.

23. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

24. A compound as defined in any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

25. A compound as defined in any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition where inhibition of thrombin is required.

26. A compound as defined in any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, for use in the treatment of thrombosis.

27. A compound of formula I as defined in any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, for use as an anticoagulant.

28. The use of a compound I as defined in any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof as active ingredient in the manufacture of a medicament for the treatment of a condition where inhibition of thrombin is required.

29. The use as claimed in Claim 28, wherein the condition is thrombosis.

30. The use of a compound defined in any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, as active ingredient in the manufacture of an anticoagulant.

31. A method of treatment of a condition where inhibition of thrombin is required which method comprises administration of a therapeutically effective amount of a compound as defined in any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, to a person suffering from, or susceptible to, such a condition.

32. A method as claimed in Claim 31, wherein the condition is thrombosis.

33. A method as claimed in Claim 31, wherein the condition is hypercoagulability in blood and tissues.

34. A process for the preparation of compounds of formula I which comprises:
(a) reaction of a compound of formula II, wherein R1, R2, R3 and Y are as defined in Claim 1 with a compound of formula III, L1-(CH2)n-B III
wherein L1 represents a suitable leaving group and n and B are as defined in Claim 1;
(b) reaction of a compound of formula IV, wherein one of R1a and R2a represents ZH and the other represents R4, and Z, R3, R4, Y, n and B are as defined in Claim 1 with a compound of formula V, L2-SO2-Ar1 V
wherein L2 is a suitable leaving group and Ar1 is as defined in Claim l;
(c) for compounds of formula I in which Y represents O or S, reaction of a compound of formula VI, wherein ya represents O or S and R1, R2 and R3 are as defined in Claim 1 with a compound of formula VII, HO-(CH2)n-B VII
wherein n and B are as defined in Claim 1;
(d) for compounds of formula I wherein B represents a structural fragment of formula Ib or Id, reaction of a compound of formula VIII, wherein B1 represents 1,4-phenylene or 1,4-cyclohexylene and R1, R2, R3, Y
and n are as defined in Claim 1 with ammonia gas;
(e) for compounds of formula I wherein B represents a structural fragment of formula Ib or Id, reduction of a compound of formula IX, wherein R1, R2, R3, Y and n are as defined in Claim 1 and B1 is as defined above;
(f) for compounds of formula I wherein B represents a structural fragment of formula Ib or Id, reaction of a compound of formula X, wherein R1, R2, R3, Y and n are as defined in Claim 1 and B1 is as defined above;
(g) for compounds of formula I wherein Y represents S(O) or S(O)2, oxidation of a corresponding compound of formula I wherein Y represents S;
(h) for compounds of formula I wherein Z represents N(R5) and R5 represents optionally substituted C1-6 alkyl, phenyl or C1-3 alkylphenyl, reaction of a corresponding compound of formula I wherein Z represents NH
with a compound of formula XI, L2-R5a XI
wherein R5a represents optionally substituted C1-6 alkyl, phenyl or C1-3 alkylphenyl and L2 is as defined above;
(i) for compounds of formula I wherein Z represents N(R5) and R5 represents C1-6 alkyl, phenyl or C1-3 alkylphenyl, all of which are substituted and/or terminated by C(O)N(R10)R11, reaction of a corresponding compound of formula I wherein R5 represents C1-6 alkyl, phenyl or C1-3 alkylphenyl, all of which are substituted and/or terminated, by C(O)OR9, and R9 is as defined in Claim 1, with a compound of formula XII, HN(R10)R11 XII
wherein R10 and R11 are as defined in Claim 1;
(j) for compounds of formula I wherein Z represents N(R5) and R5 represents C1-6 alkyl, phenyl or C1-3 alkylphenyl, all of which are substituted and/or terminated by C(O)OH, hydrolysis of a corresponding compound of formula I wherein R5 represents C1-6 alkyl, phenyl or C1-3 alkylphenyl, all of which are substituted and/or terminated by C(O)OR9 and R9 represents C1-4 alkyl;
or (k) for compounds of formula I wherein Z represents N(R5) and R5 represents (CH2)2C(O)OR9 and R9 is as defined in Claim 1, reaction of a corresponding compound of formula I wherein R5 represents H with a compound of formula XIII, CH2=CH-C(O)OR9 XIII
wherein R9 is as defined in Claim 1.