ZA200108758B - 6-[[(aryl and heteroaryl)oxy] methyl]naphthalene-2-carboximidamide derivatives, preparation and therapeutic application thereof. - Google Patents

6-[[(aryl and heteroaryl)oxy] methyl]naphthalene-2-carboximidamide derivatives, preparation and therapeutic application thereof. Download PDF

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ZA200108758B
ZA200108758B ZA200108758A ZA200108758A ZA200108758B ZA 200108758 B ZA200108758 B ZA 200108758B ZA 200108758 A ZA200108758 A ZA 200108758A ZA 200108758 A ZA200108758 A ZA 200108758A ZA 200108758 B ZA200108758 B ZA 200108758B
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formula
compound
equal
hydrogen atom
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ZA200108758A
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Chantal Alcouffe
Patrice Bellevergue
Genevieve Dellac
Christopher Latham
Gilbert Lassalle
Sergio Mallart
Valerie Martin
Christine Masson
Gary Mccort
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Sanofi Synthelabo
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Description

‘@® ®
The subject of the present invention is 6- (aryl or heteroaryl) oxymethylnaphthalene- 2-carboximidamide derivatives, their preparation and their therapeutic application.
The compounds of the invention correspond to the formula (1)
Rg
Bye
NS
Oo
Nesp A-B-C-R, (I)
NH Rs in which,
R, represents either a hydrogen atom, or an amino group, or a (C,-C,)alkyl group, or a (C,-Cq) alkoxycarbonyl group, or an -OH group, the group RENT may exist in its tautomeric form
NH
HN ,
NR, :
® 2
R, represents ® either a (C,-C¢)alkyl group which may be substituted with 1 to 3 fluorine atoms, or a cyclohexylmethyl group, or a 2,3-dihydro-1,4-benzodiox-7-ylmethyl group, or a 1,3-benzodioxolan-6-ylmethyl group, or a phenyl, benzyl or phenylethyl group which may be substituted on the phenyl group with one to three groups chosen independently from an -N(CH,), group, a trifluoromethoxy group, a methylthio group, a (C,-C,Yalkoxy group, a trifluoromethyl group, an amino group, a nitro group, a (C,-C,)alkyl group, a trifluoromethoxy group, a halogen atom, an -SO,CH, group, a hydroxyl group or a -COORy or -OCH,CO,R, group, where Ry; represents a hydrogen atom or a (C,-C,)alkyl group, or a -CH,0 group, where Q is a heterocyclic group which may be substituted with a group chosen from an ~-N (CH;), group, a trifluoromethoxy group, a (C,-C,)alkoxy group, a trifluoromethyl group, an amino group, a nitro group, a (C;-C,)alkyl group, a trifluoromethoxy group, a halogen atom, an -SO,CH; group, a hydroxyl group or a -COORy or -OCH,CO,Ry group, where Ry represents a hydrogen atom or a (C;-C,)alkyl group,
R, and Ry represent independently of each other either a hydrogen or fluorine atom,
@® or a (C,-C,)alkyl group, ® or a -COOH group, or a hydroxyl group, or an -N(CH;), group, or a -Y-CH,CO,H group, where Y represents an oxygen or nitrogen atom,
R, represents either a hydrogen atom, or a (C,-C,)alkyl group, or a -(CH,),-COORy group, where p is equal to 0, 1 or 2 and Ry represents a hydrogen atom or a (C,-C,)alkyl group,
X represents either a -(CH,).,- group, where m is equal to 0, 1 or 2, or a -CR¢R,-CH,- group or a -CH,~CR¢(R,- group, where Ry; and R, represent independently of each other a hydrogen atom or a (C,-C,)alkyl group, or an -NH-CO- or -CO-NH- group, or an -NH-CH,-, -CH,-NH-, -N(CH;)-CH,-, -CH,-N(CH;) =, -N(CH,CH;) -CH,- or -CH,-N(CH,CH;) group, i or a group —N(—C—CH,)—CH,— , where W represents an oxygen atom or an NH group,
Z represents either a -CH- group,
_ or a nitrogen atom, ® and -A-B-C- represents either an -NH-CO-NH- group, or an -NH~C (NH) -NH- group, or a -(CH,),-CO-NH- group, where n is equal to 0 or 1, or a -(CH;),-NR;-SO,- group, where gq is equal to 0, 1 or 2, and Ry represents, as above, a hydrogen atom or a (C,-C,;)alkyl group, or a -(CH;),~NH-CO- group, where g is equal to 0 or 1, or a -CH,-NH-CO-NH- group.
In accordance with the present invention, the terms hereinafter have the following meanings: - an alkyl group is a saturated, linear or branched, hydrocarbon chain, - a heterocyclic group is a hydrocarbon chain comprising a 5- or 6-membered ring, comprising 1 or two heteroatoms of oxygen, sulphur or nitrogen, this ring being aromatic or otherwise, chosen from the pyridyl, pyrimidine, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, thienyl, furyl or pyrazine group or their isomers.
In the context of the present invention, the halogen atoms are preferably chlorine and fluorine.
The compounds of the invention may comprise one or more asymmetric carbons. They may therefore
® 5 exist in the form of enantiomers or diastereoisomers. ® These enantiomers, diastereoisomers as well as mixtures thereof, including the racemic mixtures, form part of the invention.
The compounds of the invention may be provided in the form of free bases or of addition salts with pharmaceutically acceptable acids, which also form part of the invention.
The preferred compounds in the context of the present invention are those for which
R, represents either a hydrogen atom, or a (C,-Cy)alkoxycarbonyl group, or an -OH group,
R, represents either a (C,-C¢) alkyl group which may be substituted with a trifluoromethyl group, or a cyclohexylmethyl group, or a 2,3-dihydro-1,4-benzodiox-7-ylmethyl group, or a 1,3-benzodioxolan-6-ylmethyl group, or a phenyl, benzyl or phenylethyl group which may be substituted on the phenyl group with one to three groups chosen independently from an -N{(CH,), group, a trifluoromethoxy group, a methylthio group, a (C,-C,)alkoxy group, a trifluoromethyl group, an amino group, a nitro group, a (C,-C,)alkyl group, a
® 6 trifluoromethoxy group, a halogen atom, an -SO,CH, ® group, a hydroxyl group or a -COOR; or -OCH,CO,Ry group, where R; represents a hydrogen atom or a (C,-C,)alkyl group, or a -CH,0 group, where Q is a heterocyclic group which may be substituted with a group chosen from a (C,~C,) alkoxy group, an amino group or a -COORyq group, where Ry; represents a hydrogen atom or a (C,-C,)alkyl group,
R; and Ry; represent independently of each other either a hydrogen atom, or a -COOH group, or a -CHj; group,
R, represents either a hydrogen atom, or a -COOH group,
X represents either a -(CH,).- group, where m is equal to 0 or 2, or a -CR,R,~CH,- group, where Ry and R, represent independently of each other a hydrogen atom or a (C,-C,)yalkyl group, or an -NH-CO- or -NH-CH,- group, or an -NH-CH,- or -CH,-N(CH,CH3;) group,
Z represents a -CH- group, and -A-B-C- represents either an -NH-CO-NH- group, ® or a -(CH,),-CO-NH- group, where n is equal to 0 or 1, or a -(CH,),~NRy-SO,- group, where gq is equal to 0, 1 or 2, and Rg represents a hydrogen atom, or a -(CH;),~NH-CO- group, where gq is equal to 0 or 1, or a -CH,-NH-CO-NH- group, or a -CH,-CO-NH group.
According to the invention, the compounds of formula (I) may be synthesized according to scheme 1.
Scheme 1
Ry
Z X
2 5 % 0 XX + wo a —_— A-B-GP ne R. A-B-GP ne Rr {Iv) (11) ? (IIT) 3 oe
R. R, Z X
R, , ° Xn
A-BH a i C1) a a 2 NC 2 wv)
NC 3
R, (v1)
Method A or
Method B
Ry 2 %
R, xn
H C1) ° A-B-C-R,
R,-N
NH Rj (I)
PY
A compound of formula (II), in which R; and R, ® are as defined above (if R, is a -COOH group, it is in fact in the form of an ester up to the production of the compound of formula (VI)) and D represents a leaving group such as a halogen or a sulphonic ester, is reacted with a compound of formula (III), in which
R,, X, Z, A and B are as defined above (in fact, when B in the end is a ~-CO- group, it is a -CO,- group during the synthesis) and GP represents an amine- or carboxylic acid-protecting group, such as a (C,-C,)alkoxy or benzyloxy group, in the presence of a base such as potassium carbonate in an aprotic solvent, preferably acetonitrile or dimethylformamide at a temperature of between 20 and 80°C, to give a compound of formula (IV). Alternatively, this compound of formula (IV) may be prepared by a Mitsunobu reaction by condensing a compound of formula (II), in which D represents a hvdroxvl group. with a compound of formula (III) in the presence of diethyl azodicarboxylate or of 1,1'-(azodicarbonyl)dipiperidine and of a trialkyl- or triarylphosphine such as tri-n-butylphosphine or triphenylphosphine in an aprotic solvent such as 1,4- dioxane, tetrahydrofuran or toluene, at a temperature of between 0 and 60°C.
The compounds of formula (IV), in which A represents a -(CH,),~ group, where g may be equal to 0,
PY
1 or 2 and B represents an -NRg- group, where R; ® represents a hydrogen atom or a (C,-C,)alkyl group, and
GP represents an amine-protecting group such as a tert- butyloxycarbonyl, trifluorocacyl or trimethylsilyl- ethyloxycarbonyl group or any other appropriate amine- protecting group such as those described in T. Greene, “Protective Groups in Organic Synthesis”, 2nd Edition,
Wiley, NY, (1991), are deprotected under conditions known to persons skilled in the art to give a compound of formula (V).
In the case of a compound of formula (IV), in which A represents a -(CH,),- group, where n may be equal to 0 or 1 and B represents a -CO,- function, then
GP represents a carboxylic acid-protecting group such as a methyl, ethyl or tert-butyl group and the like, also known to persons skilled in the art and described in T. Greene, “Protective Groups in Organic Synthesis”, 2nd Edition, Wiley, NY, (1991). These ester compounds of formula (IV) are converted to free carboxylic acids of formula (V), where A is a -(CH,),- group, where n may be equal to 0 or 1 and BH represents a -CO,H function, by conventional methods such as saponification with hydroxide ions, hydrolysis with an inorganic or organic acid, or reaction with fluoride ions for silylated protecting groups such as trimethylsilylethyloxy- carbonyl.
® 10
The compounds of formula (V), in which A ® represents a - (CH,),~ group, where g may be equal to 0, 1 or 2 and BH represents an -NHR; group, where Rg is as defined above, may then be reacted with a sulphonyl chloride of formula R,-SO,Cl, in which R, is as defined above, then react in the presence of an organic base such as triethylamine, N-methylmorpholine or N,N- diisopropylethylamine in a solvent such as dichloromethane or dimethylformamide, at a temperature of between 0 and 60°C, to give a compound of formula (VI), in which A represents a - (CH;),~ group, where q may be equal to 0, 1 or 2, B represents an -NRyg- group and C represents an -SO,- group.
It is also possible to react a compound of formula (V), in which A represents a -(CH,),- group, where gq is equal to 0 or 1 and BH represents an amine function, - either directly with an isocyanate of formula
R,-N=C=0, in which R, is as defined above, - or first with triphosgene or an equivalent, and then with an amine of formula R,~-NH,, in which R, is as defined above, under the conditions described for the reaction with a sulphonyl chloride described above, in order to obtain a compound of formula (VI), in which A represents an -NH- or -CH,-NH- group, B represents a -CO- group and C represents an ~NH- group.
®
It is also possible to react a compound of ® formula (V), in which A represents a -(CH,),~ group and
BH represents an amine function or an -NHRg; group, - either with an acid chloride of formula R,-COCl, in which R, is as defined above, its activated ester or mixed anhydride equivalent, in the presence of an organic base, - or with a carboxylic acid of formula R,-CO,H, in which
R, is as defined above, in the presence of a coupling agent such as N’-(3-dimethylaminopropyl) -N- ethylcarbodiimide / l-hydroxybenzotriazole or [0-(7-azabenzotriazol-1-yl)-1,1, 3,3-tetramethyluronium hexafluorophosphate or another peptide coupling agent known in the art, in a solvent such as dichloromethane, dimethylformamide or in a mixture of the two, at a temperature of between 0 and 25°C, in order to obtain a compound of formula (VI), in which A represents a - (CH;) ~ group, where g is equal to 0 or 1, B represents an -NH- group and C represents a -CO- group.
To obtain a compound of formula (VI), in which A represents a -(CH,),-group, where n is equal to 0 or 1, B represents a -CO- group and C represents an -NH- group, a compound of formula (V), in which A represents a -(CH;),- group, where n is equal to 0 or 1 and BH represents a -CO,H group, is reacted with an amine of formula R,-NH,, in which R, and as defined
® above, under peptide coupling conditions set out above. ® To obtain a compound of formula (VI) in which
B-B-C- represents an -NH-C(NH)-NH- group, the compound of formula (V), in which A represents a -(CH,),- group, where gq is equal to 0 or 1 and BH represents an amine function, is reacted with an isothiocyanate of formula
R,N=C=S, in which R, is as defined above. The thiourea thus obtained is converted to guanidine by alkylation with methyl iodide, which is substituted with a source of ammonia, such as ammonium acetate or ammonium carbonate.
The compounds of formula (I) may then be obtained from these compounds of formula (VI) by functional arrangement of the nitrile group into an amidine group, for example, according to the two methods A and B described below.
Method A: the compound of formula (VI) dissolved in a mixture, saturated with hydrogen sulphide, of . triethylamine/pyridine (1:9), is treated for 20 - 36 hours at room temperature. The thioamide thus formed is alkylated with an excess of methyl iodide under reflux in acetone and the intermediate obtained is heated under reflux in an alcohol such as methanol, in the presence of a nitrogen source such as ammonium acetate or of a primary amine of formula R,;-NH,, to give a compound of formula (I).
®
Method B: the compound of formula (VI) is treated with ® hydroxylamine hydrochloride in the presence of an organic base such as triethylamine in an alcohol, preferably ethanol, at a temperature of between 40 and 70°C. The hydroxyamidine (compound of formula (I) where
R,=0H) formed is hydrogenated at a pressure of between 20 and 50 psi in an alcohol such as methanol or ethanol, in the presence of activated Raney nickel and of a few equivalents of hydrochloric or acetic acid, at a temperature of between 20 and 60°C, in order to obtain a compound of formula (I) in which R, represents a hydrogen atom.
If a compound of formula (I) is desired or R; is a (C,-C¢)alkoxycarbonyl group, a compound of formula (I) where R,=H is reacted with an alkyl chloroformate in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile in the presence of a base such as 1,1,3,3- tetramethylguanidine, triethylamine or diisopropylethylamine, at a temperature of between 0 and 25°C.
The compounds of formula (II) may be synthesized according to methodologies known to persons skilled in the art. By way of examples, a few methods of syntheses of compounds of formula (II) are given in schemes 2 and 3.
Scheme 2
CC,CH, CO,CH, 9@ —
Br NC
R, (VIII) R, (VII)
R,
D OH
-—
NC NC
R, R, (II) (R, = H) (IX)
According to scheme 2, a bromoester compound of formula (VII) is treated with a source of cyanide such as copper cyanide in dimethylformamide, at a temperature of between 50 and 140°C, or trimethylsilylcyanide in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)- palladium (0) in a solvent such as triethylamine or tributylamine, at a temperature of between 80 and 160°C, either with zinc cyanide in dimethylformamide at 80°C in the presence of palladium(0) such as tetrakis (triphenylphosphine) palladium (0) in order to obtain a nitrile of formula (VIII). The ester function may be reduced by one of the many methods known in the art, such as the reaction with lithium borohydride in an aprotic solvent such as tetrahydrofuran, at a temperature of between 0 and 80°C. The compound of formula (IX) thus obtained is then treated with a
® reagent such as phosphorus tribromide or thionyl ® chloride in a solvent such as dichloromethane or chloroform, at a temperature of between 0 and 60°C, in order to obtain the compound of formula (II), where R, represents a hydrogen atom and D represents a halogen.
The compound of formula (IX) may also be converted to a sulphonic ester such as methanesulphonate according to methods known to persons skilled in the art.
If it is desired to prepare a compound of formula (II) in which R, represents a -COORg group, where R; represents a hydrogen atom or a (C,-C,)alkyl group and D represents either a hydroxyl function or a halogen atom, the procedure is carried out, for example, according to scheme 3 where the compound of formula (II) is such that R, represents a -CO,CH,CH; group.
Scheme 3 ® CO,CH, tT OH
LT ay —_— —
Br Br
R. R Br 3 3 (VII) (x3 Ry (XI) @ CO.CH CH, CO.CH_CH, CN
NC y ! Br Br
R
(XIV) 3 } R, R, (XIII) (XII) 0
OCH, CH,
CJT
NC
Ry (XV)
CO,CH,CH,
CO,CH,CH,
Br
OH
NC
NC Ry
R; (IL) (IT)
According to scheme 3, an ester derivative of formula (VII) is first reduced to an alcohol derivative of formula (X) with, for example, lithium aluminium hydride in tetrahydrofuran, at a temperature of between -20 and -10°C. The hydroxyl function of the compound of formula (X) is converted to a halogen atom of bromine or chlorine (Hal) by conventional reactions in the art such as with phosphorus tribromide or sulphonyl chloride under conditions described earlier. A compound of formula (XI) is obtained in which the halogen atom is displaced by a source of cyanide, preferably
® tetraethylammonium cyanide in dichloromethane, at a ® temperature of between 0 and 25°C. The nitrile function of the compound of formula (XII) thus obtained is converted to an ester by treating, for example, with sulphuric acid at 95% in an alcohol of formula Rg-OH, where Rg represents a (C,-C,)alkyl group, under reflux.
A compound of formula (XIII) is obtained which is reacted with, preferably, zinc cyanide, in dimethylformamide in the presence of tetrakis (triphenylphosphine)palladium (0). A derivative of formula (XIV) is obtained which may be - either converted to a compound of formula (II), in which D represents a bromine atom and R, represents a -CO,CH,CH; group, by the action of N-bromosuccinimide in the presence of a catalytic quantity of 2,2'-azobis(2-methylpropionitrile) or benzoyl peroxide under reflux in carbon tetrachloride, - or to a glyoxalic derivative of formula (XV) by oxidation with the aid of selenium dioxide under reflux in pyridine. The selective reduction of the compounds of formula (XV), preferably with sodium borohydride at low temperature in tetrahydrofuran provides the compounds of formula (II) in which D represents a hydroxyl function and R, represents a -CO,CH,CH; group.
The compounds of formula (III) may be prepared according to scheme 4.
Scheme 4
Rs :
Z X
. NS
CK,0 y (XVIT)
Ry
Z X xn
CH,0 \ : OCH 3
Rs (XX)
Z X
CH.O x 3 NH, Rg (XVIII) © 2 X
CH.O xX 3 CHO ( (XXI) h
R R, Rg 2 X Z x | L1
EN x
Ho” NX CH,0 CH,0 Cok
NE, NH, 2 (XIX) (XXII) (XXIV)
R,
R z X 5 “1 ~N
Rg HO [Nn z x NH, HO
CO,H (XXIII) (XXV)
HO x
NHGP
(III) R, R, yA X 2 X “
HO HO xX , CO,CH,
NHGP
(III) (III)
PY
The ketones of formula (XVII) are either ® commercially available or are prepared according to methodologies described in the literature or by modifications of known procedures.
By way of example, the substituted tetralones of formula (XVII), where Z represents a -CH- group, are described in US3980699 and in European Patent
Application 0540051. The compounds of formula (XVII), where Z represents a nitrogen atom are prepared according to EP313295 and the compounds of formula (XVII), where Z represents a -CH- group and X represents an -NH-CH,- group are prepared according to a modification of the methodology described in J. Amer.
Chem. Soc. 71, p. 1901 (1949). The compounds of formula i5 (XVIII), where Z represents a -CH- group and X represents an -NH-CO or -CONH- group may be prepared according to the methodology described in Bull. Soc.
Chim. Fr., 1, p 98 (1988). The compounds of formula (XVII), where Z represents a -CH,- group and X represents a -CH,-NH- or -CH,-N(alkyl)- group may be prepared by the Pictet-Gram variation described in
Chem. Ber. 42, p 2943 (1909) and in Org. React., 6, p. 151 (1951). The compounds of formula (XXII), where Z represents a nitrogen atom and X represents an -NH-CO- group may be prepared by a modification of the methodology described in J. Chem. Soc. Perkin Trans 1,
® 20 p 353 (1991). The compounds of formula (XXII), where Z ® represents a -CH- group and X represents a -CO-NH- group may be prepared according to the method described in Chem. Pharm. Bull., 16 (3), p 455 (1968). Moreover, the indanones are sold commercially.
According to scheme 4, it is possible to react the compounds of formula (XVII), in which R;, X and Z are as defined above, - either directly by a reductive amination reaction with ammonium acetate and cyanoborohydride in methanol at room temperature, according to J. Amer. Chem. Soc. 83, p. 2897 (1971), - or indirectly in two steps, by formation of the oxime under conventional conditions followed by a reduction with iron in acetic acid or with lithium aluminium hydride or by a hydrogenation in the presence of palladium on carbon and of acetic anhydride in order to obtain a compound of formula (XVIII).
The compound of formula (XVIII) thus obtained is then demethylated either by the action of 48% hydrobromic acid under reflux or preferably with boron tribromide at a low temperature (-70 to ~20°C), in dichloromethane. The amine function of the compound of formula (XIX) then obtained is next protected with an amine-protecting group, for example a tert- butoxycarbonyl, trimethylsilylethoxycarbonyl or
® trifluorcacetyl group and the like, as described in ® Greene, “Protecting groups in organic synthesis”,
Wiley, NY, 1991. A compound of formula (III) is thus obtained in which A represents a -(CH,;)4,- group, where gq is equal to 0, B represents an -NH- group and GP represents the protecting group.
To obtain a compound of formula (III) in which A represents a -(CH;),~ group, where gq is equal to 1 and B an -NH- group, the starting ketone of formula (XVII) is first converted to an enol ether of formula (XX) by the Wittig reaction with (methoxymethyl)- triphenylphosphorane in tetrahydrofuran at a temperature of less than 0°C. The enol ether of formula (XX) is then hydrolysed to an aldehyde of formula (XXI) with the aid of an organic acid such as formic acid or p-toluenesulphonic acid in a water-tetrahydrofuran or water-dioxane mixture under reflux. The compound of formula (XXI) is then converted to an amine of formula (XXII) under the conditions described for the preparation of the compounds of formula (XVIII). The compounds of formula (XXII) are then demethylated, preferably with boron tribromide at low temperature in a solvent such as dichloromethane and the amine function of the compound of formula (XXIII) obtained is protected as described above for the compounds of formula (XIX) to give a compound of formula (III),
® where A represents a a -(CH,),~ group, where gq is equal ® to 1, B represents an -NH- group and GP is an amine- protecting group as described earlier.
The compounds of formula (XXII) may also be prepared by reacting a compound of formula (XVII) with trimethylsilyl cyanide in the presence of titanium(IV) tetrachloride in dichloromethane followed by a hydrogenation of the nitrile intermediate obtained, at a pressure of 10 to 50 psi in a solvent such as methanol in the presence of platinum oxide or of palladium on carbon.
The aldehydes of formula (XXI) may also be oxidized to carboxylic acid derivatives of formula (XXIV) by reaction with an appropriate oxidizing agent known to a person skilled in the art, such as sodium chlorite. The compounds of formula (XXIV) thus obtained are then demethylated with boron tribromide at a low temperature and then the carboxylic acid function of the compounds of formula (XXV) is esterified by one of the usual methods such as heating in methanol saturated with gaseous hydrochloric acid. A compound of formula (III) is thus obtained in which A represents a -(CH,),- group, where n is equal to 0, B represents a -CO, group and GP represents a methyl.
To obtain a compound of formula (III) in which A represents a -(CH,),~ group, where n is equal to
© 1, B represents a -CO,~- group and GP represents a methyl ® may be prepared according to scheme 5.
Scheme 5
CH,0 7 \ AQ ACY (Xvid) (xxv) oes (XXVII) €0:CTs
R, ZX —
CO,CH, (III)
According to scheme 5, the ketone of formula (XVII) may be reacted with the methyl dimethyl- phosphonoacetate anion (obtained by deprotonation with the aid of lithium bis (trimethylsilyl)amide in tetrahydrofuran, at a temperature of between -50 and 20°C) in order to obtain the o, B-unsaturated ester of formula (XXVI). The compound of formula (XXVI) is then reduced by catalytic hydrogenation to a compound of formula (XXVII), which is then demethylated with boron tribromide in dichloromethane at -70°C. A compound of formula (III) is obtained in which A represents a -(CH,),- group, where n is equal to 1, B represents a -C0,- group and GP represents a methyl.
The examples which follow illustrate the invention without limiting it. The microanalyses and
® the NMR, mass and IR spectra confirm the structure of ® the compounds obtained. The numbers for the exemplified compounds refer to those in the table given later which illustrates the chemical structures and the physical properties of a few compounds according to the invention.
Example 1: (Compound No. 32) 6-[[[8-[[[(Thiazol-4-yl]lmethyl)sulphonyl]amino]lmethyl]- 5,6,7,8-tetrahydronaphthalen-2-yljoxylmethyl]- naphthalene-2~-carboximidamide hydrochloride 1.1. Methyl 6-cyanonaphthalene-2-carboxylate 2.28 g (1.97 mmol) of tetrakis(triphenyl- phosphine)palladium (0) are added to a degassed suspension of 7.50 g (28.29 mmol) of methyl 6-bromonaphthalene-2-carboxylate and 2.01 g of (17.0 mmol) of zinc cyanide in 20 ml of dimethylformamide and the mixture is heated under nitrogen at 80°C for 16 hours. The reaction medium is evaporated to dryness and the residue is taken up in 300 ml of ethyl acetate and filtered. The filtrate is washed twice with water and then with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The residue is purified by flash chromatography on silica gel, eluting with an ethyl acetate/toluene (1:9) mixture.
® 5.20 g of white crystals are obtained. ® Melting point: 163°C
Yield: 84% 1.2. 6-(Hydroxymethyl)naphthalene-2-carbonitrile 2.06 g (94.7 mmol) of lithium borohydride are added in small quantities to a solution, cooled to 0°C, under nitrogen, of 10.0 g (47.35 mmol) of methyl 6-cyanonaphthalene-2-carboxylate in 160 ml of tetrahydrofuran and then the temperature is allowed to rise to room temperature over 4 *s hours. The reaction mixture is then heated under reflux for 2 hours, cooled to 0°C and hydrolysed by the slow addition of 100 ml of
IN hydrochloric acid. The tetrahydrofuran is evaporated off under reduced pressure and the product extracted with ethyl acetate. The organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and evaporated to dryness. The crude product is then purified by flash chromatography on silica gel, eluting with an ethyl acetate/cyclohexane (3:7) mixture. 6.72 g of product are obtained in the form of a white solid.
Melting point: 129°C
Yield: 78% 1.3. 6- (Bromomethyl) naphthalene-2-carbonitrile 4.1 ml (43.7 mmol) of phosphorus tribromide
® are added dropwise to a solution, cooled to 0°C, of ® 20.0 g (109.3 mmol) of 6-(hydroxymethyl)naphthalene- 2-carbonitrile dissolved in 600 ml of dichloromethane.
The reaction medium is then stirred at 20°C for 3 hours and then washed several times with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and then evaporated to dryness. 21.10 g of product are obtained in the form of an off-white solid.
Melting point: 138-139°C
Yield: 78% 1.4. 7-Methoxy-1- (methoxymethylene)-1,2,3,4-tetra- hydronaphthalene 19.65 g (175 mmol) of potassium tert-butoxide are introduced into a mixture of 60.0 g (175 mmol) of (methoxymethyl) triphenylphosphonium chloride in 500 ml of anhydrous tetrahydrofuran cooled to -50°C, under nitrogen and the stirring is continued at -40°C for 30 minutes. A solution of 22.0 g (125 mmol) of 7-methoxy- l-tetralone in solution in 250 ml of anhydrous tetrahydrofuran is then added dropwise. The reaction medium is then stirred at 20°C for 3 hours and then hydrolysed by slow addition of 500 ml of water. The organic phase is separated after settling and the aqueous phase 1s extracted with ethyl acetate. The organic phases are combined, washed with water, dried
® over sodium sulphate, filtered and evaporated to ® dryness. The residue obtained is triturated several times in cyclohexane and the precipitate is removed by filtration. The filtrate is evaporated to dryness and then the crude product is purified by flash chromatography on silica gel, eluting with an ethyl acetate/cyclohexane (5:95) mixture. 25.94 g of syrup are obtained, which syrup is used as it is in the next step. 1.5. 7-Methoxy-1,2, 3,4-tetrahydronaphthalene- l-carboxaldehyde
A solution of 25.50 g (125 mmol) of 7-methoxy-1- (methoxymethylene)-1,2,3,4-tetrahydro- naphthalene and 7.50 g (39.43 mmol) of para-toluene- sulphonic acid monohydrate in 200 ml of 1,4-dioxane and 50 ml of water is heated under reflux for 2 hours. The reaction medium is then evaporated under reduced pressure and the residue is taken up in 250 ml of ethyl acetate. The solution is washed twice with water and the organic phase is dried over sodium sulphate, filtered and then evaporated to dryness. 24.1 g of a pale yellow oil are obtained, which oil is used without further purification in the next step. 1.6. 7-Methoxy-1,2,3,4-tetrahydronaphthalene- 1-carboxaldehyde oxime
A solution of 28.70 g (150 mmol) of
® 7-methoxy-1,2,3,4-tetrahydronaphthalene- ® l-carboxaldehyde dissolved in 20 ml of ethanol is added, at room temperature, to a solution of 11.10 g (160 mmol) of hydroxylamine hydrochloride and 25 ml (180 mmol) of triethylamine in 100 ml of absolute ethanol. The mixture is then heated under reflux for two hours and then evaporated to dryness. The residue is taken up in ethyl acetate and the solution is washed with a 1M aqueous citric acid solution, and then with a saturated aqueous ammonium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness. 28.04 g of product are obtained in the form of a white solid.
Melting point: 147°C
Yield: 93% 1.7. 7-Methoxy-1,2,3,4-tetrahydronaphthalene-1- methanamine 49 ml (49 mmol) of a 1M lithium aluminium hydride solution in tetrahydrofuran are added dropwise to a solution of 10.0 g (48.78 mmol) of 7-methoxy- 1,2,3,4-tetrahydronaphthalene-1l-carboxyaldehyde oxime in 200 ml of anhydrous THF at room temperature. The reaction medium is stirred at room temperature for 16 hours and then hydrolysed by successive addition of 1.9 ml of water, 1.9 ml of IN sodium hydroxide and then
® 5.6 ml of water. 50 g of magnesium sulphate are added ® and the mixture is stirred to 5 minutes and then filtered. The salts are rinsed with dichloromethane and the filtrates are evaporated to dryness. The residue is taken up in ethyl acetate and the solution is washed successively with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution and finally with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness. 8.99 g of product are obtained in the form of a colourless oil.
Yield: 88%. 1.8. 8- (Aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-o01l hydrobromide 109 ml (109 mmol) of a 1M boron tribromide solution in dichloromethane are added dropwise to a solution, cooled to -78°C, of 9.50 g (49.7 mmol) of 7-methoxy-1,2,3,4-tetrahydronaphthalene-l-methanamine in 49 ml of dichloromethane. The reaction mixture is stirred for 30 minutes at -78°C and then for 30 minutes at room temperature. The mixture is hydrolysed at -78°C by the dropwise addition of 100 ml of methanol and then stirred at 20°C for one hour. The medium is evaporated to dryness and then taken up in toluene and re-evaporated to dryness.
® 30 12.40 g of product are obtained in the form of a ® hygroscopic amorphous solid.
Yield: 97%
Melting point (hydrochloride): 181-183°C 1.9. 1,1-Dimethylethyl [(7-hydroxy-1,2,3,4-tetrahydro- naphthalen-1l-yl)methyl]carbamate 11.70 g (53.67 mmol) of di-tert-butyl dicarbonate are added to a mixture of 11.74 g (45.50 mmol) of 8-(aminomethyl)-5,6,7,8- tetrahydronaphthalen-2-ol hydrobromide in 360 ml of
THF, with stirring at 20°C. 12.7 ml (91 mmol) of triethylamine are then added dropwise and the mixture is stirred for 4 hours at 20°C. The reaction medium is then evaporated to dryness and the residue is taken up in 300 ml of ethyl acetate. The solution is washed with water and the organic phase is dried over sodium sulphate, filtered and then evaporated to dryness. The crude product is then purified by flash chromatography on silica gel, eluting with an ethyl acetate/- cyclohexane (1:9) mixture. 8.15 g of product are obtained in the form of a gum.
Yield: 68% 1.10. 1,1-Dimethylethyl [[7-{(6-cyanonaphthalen- 2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen- l-yl]lmethyl] carbamate
A mixture of 4.40 g (17.8 mmol) of
® 6- (bromomethyl)naphthalene-2-carbonitrile, 4.0 g ® (14.4 mmol) of 1,l-dimethylethyl [(7-hydroxy- 1,2,3,4-tetrahydronaphthalen-1-yl)methyl] carbamate and 3.20 g (23.3 mmol) of potassium carbonate in 120 ml of acetonitrile is heated at reflux for 6 hours. The reaction medium is evaporated to dryness and the crude product is purified by flash chromatography on silica gel, eluting with an ethyl acetate/cyclohexane (1:4) mixture. 5.60 g of product are obtained in the form of a white solid.
Melting point: 122°C
Yield: 87% 1.11. 6-[[{8-(Aminomethyl)-5,6,7,8-tetrahydro- naphthalen-2-yl]oxy]lmethyl]naphthalene- 2-carbonitrile hydrochloride 4.70 g (10.63 mmol) of 1,1-dimethylethyl [[7-[ (6-cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetra- hydronaphthalen-1-yl]methyl] carbamate in 100 ml of dichloromethane and 10 ml of 4N anhydrous hydrochloric acid in dioxane are stirred for 14 hours at 20°C. The reaction medium is evaporated to dryness and the solid is triturated in diethyl ether, drained and dried under vacuum. 3.80 g of product are obtained in the form of a white solid.
®
Melting point: 149-150°C ® Yield: 95% 1.12. Thiazol-4-ylmethyl ethanethiocate
A mixture of 3.50 g (19.57 mmol) of 4-chloromethylthiazole hydrochloride and 2.70 g (19.57 mmol) of potassium carbonate is stirred for 15 minutes at 0°C. 2.24 g (19.57 mmol) of potassium thioacetate are then added and the stirring is continued at room temperature for 4 hours. The reaction medium is evaporated to dryness under reduced pressure and the residue is taken up in diethyl ether. The solution is washed with ice-cold water and then with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, filtered and then evaporated to dryness. The product is purified by flash chromatography on silica gel, eluting with an ethyl acetate/cyclohexane (3:7) mixture, giving 2.35 g of the expected product in the form of an oil.
Yield: 69% : 1.13. Thiazole-4-methanesulphonyl chloride hydrochloride 0.73 ml (40.56 mmol) of water is added to a solution, cooled to 0°C, of 2.34 g (13.53 mmol) of thiazol-4-ylmethyl ethanethiocate in 12 ml of acetic acid followed dropwise by 3.26 ml (40.56 mmol) of thionyl chloride and the temperature is allowed to rise
® 33 to 20°C and then the mixture is stirred at this ® temperature for 4 hours. The reaction medium is evaporated to dryness and the solid is triturated in ethyl acetate and then in diethyl ether and it is then dried under vacuum. 1.95 g of the expected product are obtained in the form of a pale yellow solid.
Melting point: 170°C
Yield: 61% 1.14. N-[[7-[(6-Cyanonaphthalen-2-yl)methoxyl]~ 1,2,3,4-tetrahydronaphthalen-1-yl]methyl]- thiazole-4-methanesulphonamide 0.34 g (1.45 mmol) of thiazole-4-methane- sulphonyl chloride hydrochloride is added to a solution of 0.41 g (1.20 mmol) of 6-[[[8-(aminomethyl) - 5,6,7,8-tetrahydronaphthalen-2-yl]oxylmethyl]- naphthalene-2-carbonitrile in 20 ml of dichloromethane, cooled to 0°C, followed by 0.44 ml (3.30 mmol) of triethylamine and the mixture is stirred at room temperature for 16 hours. The reaction medium is then diluted in 100 ml of dichloromethane and the solution is washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and then evaporated. The crude product is then purified by flash chromatography on silica gel, eluting with a methanol/dichloromethane
TY
(2:98) mixture containing traces of concentrated _ aqueous ammonia. 0.304 g of product is obtained in the form of a foam / white gum.
Yield: 50% 1.15. N’-Hydroxy-6-[[[8-[[[(thiazol~4-ylmethyl)- sulphonyl]aminolmethyl]-5,6,7,8-tetrahydro- naphthalen-2-ylloxylmethyl]lnaphthalene- 2~carboximidamide
A mixture of 0.30 g (0.60 mmol) of N-[[7-[(6- cyanonaphthalen-2-yl)methoxyl-1,2,3,4-tetrahydro- naphthalen-1-ylimethyl]lthiazole-4-methanesulphonamide, 0.103 g (1.49 mmol) of hydroxylamine hydrochloride and 0.20 ml (1.49 mmol) of triethylamine in 30 ml of absolute ethanol is heated under reflux for 8 hours.
The reaction medium is then evaporated to dryness and the solid is triturated in water, drained and then dried under vacuum. 0.319 g of product is obtained in the form of a white solid.
Melting point: 140°C
Yield: 99% 1.16. 6-[[[8-[[[(Thiazol-4-ylmethyl)sulphonyl]lamino]- methyl]-5,6,7,8-tetrahydronaphthalen-2-yljoxy]- methyl)naphthalene-2-carboximidamide hydrochloride
@®
A mixture of 0.31 g (0.576 mmol) of ® N’~-hydroxy-6-[[[8-[[[ (thiazol-4-ylmethyl)sulphonyl]- amino]methyl]-5,6,7,8~-tetrahydronaphthalen-2-yl]oxy]- methyl ]naphthalene-2-carboximidamide in 30 ml of methanol, 3 ml of acetic acid and 11.8 ml of anhydrous hydrochloric acid in isopropanol is hydrogenated in a
Parr apparatus at a pressure of 40 psi for 12 hours in the presence of 0.25 g of activated Raney nickel. The reaction medium is then filtered and the filtrate is evaporated to dryness. The crude product is purified by
Cl8 reversed phase flash chromatography; eluting with a methanol gradient from 10 to 50% in N/1000 aqueous hydrochloric acid. 0.164 g of product is obtained in the form of a white solid.
Melting point: 135°C 1.16. 6-[[[8-[[[(Thiazol-4~ylmethyl)sulphonyl]amino]- methyl]-5,6,7,8-tetrahydronaphthalen-2-yl]oxy]- methyl] naphthalene-2-carboximidamide hydrochloride
A mixture of 0.31 g (0.576 mmol) of
N’-hydroxy-6-[[[8-[[[(thiazol-4-ylmethyl)sulphonyl)- amino]methyl]-5,6,7,8-tetrahydronaphthalen-2-ylloxy]- methyl]lnaphthalene-2-carboximidamide in 30 ml of methanol, 3 ml of acetic acid and 11.8 ml of anhydrous hydrochloric acid in isopropanol is hydrogenated in a pe 20018758
Parr apparatus at a pressure of 40 psi for 12 hours in ® the presence of 0.25 g of activated Raney nickel. The reaction medium is then filtered and the filtrate is evaporated to dryness. The crude product is purified by
Cl8 reversed phase flash chromatography, eluting with a methanol gradient from 10 to 50% in N/1000 aqueous hydrochloric acid. 0.164 g of product is obtained in the form of a white solid.
Melting point: 135°C
Example 2: (Compound No. 17)
N-[7-[[6- (Aminoiminomethyl) naphthalen-2-yl]methoxy]- 1,2,3,4-tetrahydronaphthalen-1-yl]-3-methoxybenzene- acetamide hydrochloride 2.1. 7-Methoxy-1,2,3,4-tetrahydronaphthalen-l-amine 5.10 g (81.16 mmol) of sodium cyanoborohydride are added to a mixture of 17.60 g (99.89 mmol) of 7-methoxy-l-tetralone and 77.0 g (1 mol) of anhydrous ammonium acetate in 500 ml of methanol at room temperature and the stirring is continued at this temperature for 96 hours. The methanol is evaporated under reduced pressure and it is replaced with 400 ml of diethyl ether. The mixture is cooled to 0°C and is then hydrolysed by the addition of 6N hydrochloric acid to pH 1. The aqueous phase is washed with 3 times 100 ml of ether and then separated
® and its pH adjusted to 9 with the aid of concentrated sodium hydroxide. The product is then extracted with ether and the organic phases are dried over sodium sulphate, filtered and then evaporated to dryness. 16.13 g of product are obtained in the form of a colourless oil.
Yield: 93% 2.2. 1,1-Dimethylethyl (7-methoxy-1,2,3,4-tetrahydro- naphthalen-1-yl) carbamate 16.0 g (90.4 mmol) of 7-methoxy-1,2,3,4- tetrahydronaphthalen-l-amine are introduced in small quantities into 300 ml of 48% hydrobromic acid and the mixture is heated under reflux for 15 hours. The reaction medium is evaporated to dryness and the residue is taken up in 250 ml of tetrahydrofuran. 21.80 g (100.0 mmol) of di-tert-butyl dicarbonate are added followed, dropwise, by 30 ml (215.24 mmol) of triethylamine and the mixture is stirred for 17 hours at room temperature. The pH of the medium is adjusted to 5-6 with acetic acid and then the medium is extracted with ethyl acetate. The organic phase is washed with water and then dried over sodium sulphate, filtered and then evaporated to dryness. After recrystallization from ethanol, 21.07 g of a white solid are obtained.
Melting point: 72-73°C
®
Yield: 88% ® 2.3. 1,1-Dimethylethyl [7-[(6-cyanonaphthalen- 2-yl)methoxyl]-1,2,3,4-tetrahydronaphthalen- l-yl]carbamate
A mixture of 11.50 g (46.8 mmol) of 6- (bromomethyl)naphthalene-2-carbonitrile, 10.0 g (38.02 mmol) of 1,1-dimethylethyl (7-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)carbamate and 8.50 g (61.51 mmol) of potassium carbonate in 300 ml of acetonitrile is heated under reflux for 6 hours. The reaction mixture is then evaporated to dryness and the crude product is purified by flash chromatography on silica gel, eluting with an ethyl acetate/cyclohexane (2:8) mixture. 14.13 g of product are obtained in the form of a white solid.
Melting point: 114-115°C
Yield: 87% 2.4. 6-[[8-Amino-5,6,7,8-tetrahydronaphthalen- 2-yl)oxylmethyl]naphthalene-2-carbonitrile hydrochloride
A stream of gaseous hydrochloric acid is bubbled for 5 minutes through a solution, cooled to 5°C, of 1.0 g (2.33 mmol) of 1,1l-dimethylethyl [7-[ (6-cyanonaphthalen-2-yl)methoxy]-1,2, 3, 4- tetrahydronaphthalen-l-yl]carbamate in 80 ml of
® dichloromethane and then the mixture is stirred at room ® temperature for 5 hours. The reaction medium is then evaporated to dryness and the solid is triturated in diethyl ether, drained and then dried under vacuum. 0.850 g of product is obtained.
Melting point: 222-223°C
Yield: 100% 2.5. N-[7-[(6-Cyanonaphthalen-2-yl)methoxyl]-1,2,3,4- tetrahydronaphthalen-1-yl]-3-methoxybenzene- acetamide 0.66 g (1.81 mmol) of 6-[[8-amino-5,6,7,8- tetrahydronaphthalen-2-yl)oxylmethyl]lnaphthalene- 2-carbonitrile hydrochloride, 0.244 g (1.81 mmol) of l-hydroxybenzotriazole and then 0.90 ml (5.17 mmol) of
N,N-diisopropyl-N-ethylamine are added to a solution of 0.30 g (1.81 mmol) of 3-methoxylphenylacetic acid in 10 ml of dichloromethane. The mixture is cooled to 0°C and 0.38 g (1.98 mmol) of N’-(3-dimethylaminopropyl)-
N-ethylcarbodiimide is then added. The temperature is allowed to rise to room temperature and the mixture is stirred for 14 hours. The reaction medium is then diluted in 150 ml of ethyl acetate and the solution is washed with a 1N aqueous citric acid solution (3 x 50 ml), with water (50 ml), with a saturated aqueous sodium bicarbonate solution (3 x 50 ml) and finally with a saturated sodium chloride solution
® (50 ml). The organic phase is dried over sodium ® sulphate, filtered and then evaporated to dryness. The crude product is purified by flash chromatography on silica gel, eluting with a methanol/dichloromethane (5:95) mixture. 0.802 g of product is obtained.
Melting point: 146°C
Yield: 92% 2.6. N-[7-[[6-[Amino (hydroxyimino)methyl]lnaphthalen- 2-yl]lmethoxy]-1,2,3,4-tetrahydronaphthalen-1-yl]- 3-methoxybenzeneacetamide
A mixture of 0.793 g (1.66 mmol) of N-[7-[ (6- cyanonaphthalen-2-yl)methoxyl-1,2,3,4- tetrahydronaphthalen-1-yl]-3-methoxybenzeneacetamide, 0.30 g (4.31 mmol) of hydroxylamine hydrochloride and 0.60 ml (4.31 mmol) of triethylamine in 50 ml of absolute ethanol is heated under reflux for 6 hours.
The reaction medium is then evaporated to dryness and the solid is triturated in 10 ml of water, drained and dried under vacuum. 0.768 g of product is obtained in the form of a white solid.
Yield: 90% 2.7. N-[7-{[6-(Aminoiminomethyl)naphthalen- 2-yl)methoxyl-1,2,3,4-tetrahydronaphthalen-1-yl]- 3-methoxybenzeneacetamide hydrochloride 0.760 g (1.49 mmol) of N-[7-[[6-[amino-
® (hydroxyimino)methyl]naphthalen-2-yl]methoxy]-1,2,3,4- ® tetrahydronaphthalen-1-yl]-3-methoxybenzeneacetamide is stirred for 10 minutes in 15 ml of 0.1N hydrochloric isopropanol and then evaporated to dryness. This hydrochloride is then dissolved in 30 ml of methanol and 3 ml of acetic acid and the solution is loaded into a Parr apparatus and hydrogenated for 5 hours at 40°C at a pressure of 40 psi in the presence of 0.50 g of activated Raney nickel. The reaction mixture is then filtered on celite and the filtrate is evaporated to dryness. The crude product is purified by C18 reversed phase HPLC, eluting with an acetonitrile gradient from 0 to 100% over 180 minutes in N/1000 aqueous hydrochloric acid. 0.150 g of product is obtained.
Melting point: 120°C
Yield: 20%
Example 3: (Compound No. 5) 6-[[[8-[[[(Pyridin-3-ylmethyl)amino]carbonyl]amino]- 5. 6.7 8-tetrahydronaphthalen-2-yl]oxy]methyl]- naphthalene-2-carboximidamide hydrochloride 3.1. 6-[[[8-[[[(Pyridin-3-ylmethyl)amino]carbonyl]- amino] -5,6,7,8-tetrahydronaphthalen-2-yl]oxy]- methyl ]naphthalene-2-carbonitrile 0.356 g (1.20 mmol) of bis(trichloromethyl)- carbonate is added to a suspension, cooled to 5°C, of
® 0.73 g (2.00 mmol) of 6-[[(8-amino-5,6,7,8-tetrahydro- ® naphthalen-2-yl)oxylmethyl]lnaphthalene-2-carbonitrile hydrochloride in 20 ml of 1,4-dioxane, followed by 1.40 ml (10 mmol) of triethylamine. The mixture is stirred at room temperature for 30 minutes and then 0.220 g (2.03 mmol) of 3-aminomethylpyridine is added to the isocyanate thus formed. The reaction mixture is stirred for 15 hours at 20°C and then 75 ml of water are added and the mixture is extracted with dichloromethane (3 x 100 ml). The organic phases are combined, washed with a saturated aqueous sodium chloride solution, dried over Na,S0O,, filtered and evaporated to dryness. The crude product is purified by flash chromatography on silica gel, eluting with a methanol/dichloromethane (5:95) mixture. 0.707 g of product is obtained.
Yield: 76% 3.2. 6-[[[8-[[[(Pyridin-3-ylmethyl)amino]carbonyl]- amino]}-5,6,7,8-tetrahydronaphthalen-2-ylloxyl- methyl]naphthalene-2~carboximidamide hydrochloride
A mixture of 0.265 g (3.81 mmol) of hydroxylamine hydrochloride, 0.707 g (1.53 mmol) of 6-[[[8-[[[(pyridin-3-ylmethyl)amino]carbonyl]amino]- 5,6,7,8-tetrahydronaphthalen-2-yl]oxy]methyl]- naphthalene-2-carbonitrile and 0.64 ml (4.60 mmol) of
® 43 triethylamine, in 15 ml of absolute ethanol, is heated ® under reflux for 5 hours. The reaction mixture is evaporated to dryness and the solid obtained is triturated in 10 ml of water, drained and then dried under vacuum. The residue is taken up in 20 ml of 0.1N hydrochloric isopropanol and then evaporated to dryness. The hydrochloride is dissolved in 50 ml of methanol/acetic acid (9:1) and the solution is locaded into a Parr apparatus with 0.80 g of activated Raney nickel and hydrogenated at a pressure of 40 psi for 13 hours at 20°C. The reaction mixture is filtered and the filtrate is evaporated. The product is purified by
C18 reversed phase flash chromatography, eluting with an acetonitrile gradient from 20 to 100% in 0.001N aqueous hydrochloric acid. 0.315 g of product is obtained in the form of a white solid (dihydrochloride).
Melting point: 175°C (decomposition)
Yield: 37%
Example 4: (Compound No. 13) 6-[[[8-[[[[ (3-Methoxyphenyl)methyl]sulphonyl]amino]- methyl]-5,6,7,8-tetrahydronaphthalen-2-yl]oxy]methyl]- naphthalene-2-carboximidamide hydrochloride 4.1. 3-Methoxybenzenemethanesulphonyl chloride
A mixture of 10.0 g (49.7 mmol) of 3-methoxy- benzyl bromide, 6.30 g (50.0 mmol) of sodium sulphite
® and 0.16 g (0.50 mmol) of tetra-n-butylammonium bromide ® in 35 ml of water is heated at 95°C for 2 hours. The reaction mixture is then stirred at room temperature overnight and then evaporated to dryness. 10.5 g of the 16.5 g of the solid obtained are suspended in 135 ml of dichloromethane and 20.1 g (96.5 mmol) of phosphorus pentachloride are added in small quantities at room temperature. The reaction medium is stirred at this temperature for 1 hour and then evaporated to dryness.
The residue is taken up in ethyl acetate and the solution is washed with water and then with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. 6.95 g of product are obtained in the form of an oil.
Yield: 98% 4.2. N-[[7-[(6-Cyanonaphthalen-2-yl)methoxy]- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl]- 3-methoxybenzenemethanesulphonamide 0.60 g (2.72 mmol) of 3-methoxybenzene- methanesulphonyl chloride in solution in 10 ml of dichloromethane is added to a mixture of 0.644 g (1.17 mmol) of 6-[[[8-(aminomethyl)-5,6,7,8-tetrahydro- naphthalen-2-yl]loxylmethyl]naphthalene-2-carbonitrile hydrochloride and 0.68 ml (4.90 mmol) of triethylamine in 50 ml of dichloromethane and the mixture is stirred
® at 20°C for 3 hours. The reaction medium is then ® evaporated to dryness and the residue is taken up in ethyl acetate. This solution is washed successively with a 1M aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and then a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, filtered and ~ evaporated to dryness. The product is purified by flash chromatography on silica gel, eluting with a methanol/dichloromethane (2:98) mixture. 0.382 g of product is obtained in the form of a white foam.
Yield: 60% 4.3. 6-[[[8-[[[[ (3-Methoxyphenyl)methyl]sulphonyl]- amino]methyl] -5,6,7,8-tetrahydronaphthalen- 2-ylloxylmethyl lnaphthalene-2-carboximidamide hydrochloride
A mixture of 0.382 g (0.73 mmol) of
N-[[7-[ (6-cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetra- hydronaphthalen-1-yllmethyl]-3-methoxybenzenemethane- sulphonamide, 0.13 g (1.87 mmol) of hydroxylamine hydrochloride and 0.28 ml (2.0 mmol) of triethylamine is heated under reflux for 6 hours. The reaction mixture is then evaporated to dryness and the solid is triturated in 10 ml of water, drained and dried under vacuum. The product is taken up in 10 ml of O.1N

Claims (5)

  1. C3 Claims
    ® 1. Compounds of formula (I) R, , R, LI ° AN NH Rs in which, R, represents either a hydrogen atom, or an amino group, or a (C,-C,)alkyl group, or a (C,-C¢)alkoxycarbonyl group, or an -OH group, it being possible for the group R—N—r— to exist in NH its tautomeric form HN , NR, R, represents either a (C,-C¢)alkyl group which may be substituted with 1 to 3 fluorine atoms, or a cyclohexylmethyl group, or a 2,3-dihydro-1,4-benzodiox-7-ylmethyl group, or a 1,3-benzodioxolan-6-ylmethyl group,
    ® 92 or a phenyl, benzyl or phenylethyl group which may ® be substituted on the phenyl group with one to three groups chosen independently from an -N(CH;), group, a trifluoromethoxy group, a methylthio group, a (C,-C,) alkoxy group, a trifluoromethyl group, an amino group, a nitro group, a (C,-C,)alkyl group, a trifluoromethoxy group, a halogen atom, an -SO,CH; group, a hydroxyl group or a -COORy or ~OCH,CO,Ry group, where Rg; represents a hydrogen atom or a (C,-C,)alkyl group, or a -CH,Q group, where Q is a heterocyclic group which may be substituted with a group chosen from an -N(CH,), group, a trifluoromethoxy group, a (C,-C;)alkoxy group, a trifluoromethyl group, an amino group, a nitro group, a (C,-C,)alkyl group, a trifluoromethoxy group, a halogen atom, an -SO,CH; group, a hydroxyl group or a -COORg or -OCH,CO,Rg group, where Ry represents a hydrogen atom or a (C,-C,)alkyl group, R; and R; represent independently of each other either a hydrogen or fluorine atom, or a (C;-C,)alkyl group, or a —-COOH group, or a hydroxyl group, or an -N(CH;), group, or a -Y-CH,CO,H group, where Y represents an oxygen or nitrogen atom,
    @
    R, represents ® either a hydrogen atom, or a (C,-C,)alkyl group, or a -(CH,),-COORs group, where p is equal to GQ, 1 or 2 and R; represents a hydrogen atom or a (C,-C,)alkyl group, X represents either a -(CH,),- group, where m is equal to 0, 1 or 2,
    or a -CR¢R,-CH,- group or a -CH,-CR¢R;,- group, where Ry, and R,; represent independently of each other a hydrogen atom or a (C,-C,)alkyl group,
    or an -NH-CO- or -CO-NH- group,
    or an -NE-CH,-, -CH,-NH-, -N(CH;)-CH,-, -CH,-N(CH,;)-,
    -N (CH,CH;) -CH,- or -CH,-N(CH,CH;) group, w or a group —N(—=C—CH,;)—CH,— , where W represents an oxygen atom or an NH group, Z represents either a -CH- group,
    or a nitrogen atom,
    and -A-B-C- represents either an -NH-CO-NH- group, or an -NH-C (NH) -NH- group, or a -(CH,),-CO-NH- group, where n is equal to 0 or
    ® 94 or a -(CH;) 4 NRy-SO,- group, where g is equal to O, _ l or 2, and Ry represents, as above, a hydrogen atom or a (C,-Cy)alkyl group, or a -(CH,),~NH-CO~ group, where g is equal to 0 or 1, or a -CH,-NH-CO-NH- group, in the form of a racemate or of pure enantiomers or of mixtures of enantiomers or alternatively in the form of a free acid or base or of pharmaceutically acceptable addition salts.
  2. 2. Compounds according to Claim 1, characterized in that R, represents either a hydrogen atom, or a (C,-Cq)alkoxycarbonyl group, or an -OH group, R, represents either a (C,-C¢)alkyl group which may be substituted with a trifluoromethyl group, or a cyclohexylmethyl group, or a 2,3-dihydro-1,4-benzodiox-7-ylmethyl group, or a 1,3-benzodioxolan-6-ylmethyl group, or a phenyl, benzyl or phenylethyl group which may be substituted on the phenyl group with one to three groups chosen independently from an -N(CH;), group, a trifluoromethoxy group, a methylthio group, a bd 95 (C,~-C,)alkoxy group, a trifluoromethyl group, an amino ® group, a nitro group, a (C,-C,)alkyl group, a trifluoromethoxy group, a halogen atom, an -SO,CH; group, a hydroxyl group or a -COORy or -OCH,CO,Ry group, where Ry; represents a hydrogen atom or a (C,-C,)alkyl group, or a -CH,Q group, where Q is a heterocyclic group which may be substituted with a group chosen from a (C,-C,)alkoxy group, an amino group or a -COOR; group, where R; represents a hydrogen atom or a (C,-C,)alkyl group, R, and R, represent independently of each other either a hydrogen atom, or a —~COOH group, or a -CH; group, R, represents either a hydrogen atom, or a -COOH group, X represents either a -(CH,),- group, where m is equal to 0 or 2, or a —-CR¢(R,-CH,- group, where Ry and R, represent independently of each other a hydrogen atom or a (C,-C4)alkyl group, or an -NH-CO- or -NH-CH,- group, or an -NH-CH,- or -CH,-N(CH,CH;) group,
    ® S96 Z represents a -CH- group, ® and -A-B-C- represents either an -NH-CO-NH- group, or a -(CH;),-CO-NH- group, where n is equal to 0 or 1, or a -(CH;),~NRyg-SO,- group, where gq is equal to 0, 1 or 2, and Ry represents a hydrogen atom, or a -(CH,),~NH-CO- group, where gq is equal to 0 or 1, or a -CH,~NH-CO-NH- group, or a -CH,-CO-NH group, in the form of a racemate or of pure enantiomers or of mixtures of enantiomers or alternatively in the form of a free acid or base or of pharmaceutically acceptable addition salts.
  3. 3. Process for preparing a compound of formula (I) according to Claim 1 or 2, characterized in that a compound of formula (II) R, D NC R, in which R; and R, are as defined in Claim 1 or 2 and D represents a leaving group is reacted with a compound of formula (III)
    Rs Z ® | X (III) NS HO A-B-GP in which Ry, X, Z, A and B are as defined in Claim 1 or 2 and GP represents an amine- or carboxylic acid- protecting group, in the presence of a base to give a compound of formula (IV) R S\_7 " R, NN 0 NC R (IV) 3 which is deprotected to give a compound of formula (V) Rs Z X R, ANN 0 NC (V) Rj which is alternatively reacted with the following different reagents, to give a compound of formula (VI):
    @
    , . R z ’ JOO ° NS QE en NC Rj, - a sulphonyl chloride of formula R,-SO,Cl, where R, is as defined in Claim 1, when, in formula (V), A represents a -(CH;),~ group, where q may be equal to 0, 1 or 2 and BH represents an -NHRg; group, where Ry is as defined in Claim 1, to give a compound of formula (VI), in which A represents a -(CH;),~ group, where q may be equal to 0, 1 or 2, B represents an -NRg- group and C represents an -S0,- group, - an isocyanate of formula R,-N=C=0, or first triphosgene, and then an amine of formula R,-NH,, where R, is in both cases as defined in Claim 1, when, in formula (V), A represents a -(CH,;),~ group, where g may be equal to 0 or 1 and BH represents an amine function, to give a compound of formula (VI), in which A represents an -NH- or -CH,-NH- group, B represents a -CO- group and C represents an -NH- group, - an acid chloride of formula R,-COCl, in the presence of an organic base or alternatively a carboxylic acid of formula R,-CO,H, in the presence of a coupling agent, where R, is in both cases as defined in Claim 1, when,
    @
    in formula (V), A represents a -(CH,),~ group, where gq Ly may be equal to 0 or 1 and BH represents an amine function, to give a compound of formula (VI), in which A represents a -(CH;)4,- group, where gq may be equal to O or 1, B represents an -NH- group and C represents a -CO- group, - an amine of formula R,-NH,, where R, is as defined in Claim 1, when, in formula (V), A represents a -(CH,), - group, where n may be equal to 0 or 1 and BH represents a -CO,H group, to give a compound of formula (VI), in which A represents a -(CH,),- group, where n may be equal to 0 or 1, B represents a -CO- group and C represents an -NH- group, - an isothiocyanate of formula R,N=C=S, in which R, is as defined in Claim 1, when in formula (V), A represents a -(CH,),- group, where g is equal to 0 or 1 and BH represents an amine function, to give a thiourea which is converted to guanidine by alkylation with methyl iodide, and which is then substituted with a source of ammonia, to give a compound of formula (VI), in which A-B-C- represents an -NH-C(NH)-NH- group, which compound of formula (VI) is subjected to a functional arrangement of the nitrile group into a hydroxylamidine group, compound of formula (I), where R; is an OH group, and which is then reduced to an amidine to give a compound of formula (I), which is optionally
    @ reacted with an alkyl chloroformate in the presence of gp) a base to give a compound of formula (I), where R; is a (C,-C¢) alkoxycarbonyl group.
  4. 4. Medicament, characterized in that it contains a compound according to Claim 1 or 2.
  5. 5. Pharmaceutical composition characterized in that it contains a compound according to Claim 1 or 2 in combination with any pharmaceutically acceptable excipient.
ZA200108758A 1999-05-04 2001-10-24 6-[[(aryl and heteroaryl)oxy] methyl]naphthalene-2-carboximidamide derivatives, preparation and therapeutic application thereof. ZA200108758B (en)

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