DD294715A5 - PROCESS FOR THE PREPARATION OF PYRANYLCYANO-GUANIDINE DERIVATIVES - Google Patents

Abstract

A process for the preparation of pyranyl cyanoguanidine derivatives of the general formula (I) in which R 1 is a radical of the formulas is described. These compounds have a potassium channel activation effect and are suitable, for example, as cardiovascular active substances, in particular as anti-analgesic agents. Formula (I) and formulas {pyranylcyanoguanidine derivatives; Potassium channel-activating effect; cardiovascular agents; antiischemic agents}

Description

Title of the invention; Process for the preparation of pvranvlcovanoauanidine derivatives Field of application of the invention

The application of the present invention is in the field of potassium channel activating drugs.

characteristics dt!> btk & n ^ h * 3 / a * dfs of T

Publications which underlie the present invention as prior art are currently unknown.

Object of the invention and Qc / · / (ςunί, dt j Lj / e ^ tt i dt

The invention has for its object to provide new drugs with Kaiium channel activation effect, for example, with cardiovascular action.

The invention relates to a process for the preparation of pyranyl cyanoguanidine derivatives of general formula I.

Ji99? 15

(D

in which a, b and c are each carbon atoms or one of the radicals a, b and c may have the meaning nitrogen or -NO- and the other carbon atoms; R _{1 is} a radical of the formulas

or

= NCN;

means;

R is hydrogen, hydroxyl or the radical of the formula -OCCH ₀

Il ³ o

means;

R ₃ and R _{4 are} each independently hydrogen, alkyl or arylalkyl, or R ₃ and R _{4 taken} together with the carbon atom to which they are attached form a 5- to 7-membered carbocyclic ring;

R ₅ is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, cycloalkylalkyl, -CN, -NO ₂ , -COR,. -COOR, -CONHR, -CONR ₂ , -CF ₃ , S-alkyl, -SO-alkyl, -SO ₂ -alkyl,

ί? -P (O-alkyl) ₂ , -P

-J

Halogen, amino, substituted amino, O-alkyl, OCF OCH ₂ CF ₃ , -o-C0-alkyl, -OCONR-alkyl, -NRCO-alkyl, -NRCOO-alkyl and -NRCONR ₂ , wherein R in the above groups are each hydrogen, Alkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl) alkyl;

! 5 / J </? 75

R _{6 is selected} from H, alkyl, OH, O-alkyl, amino, substituted amino, CN and NO ₂ ;

R ₇ and R _{8 are} each independently selected from hydrogen, alkyl, alkenyl, aryl, heterocyclo, (heterocyclo) alkyl, arylalkyl, cycloalkyl, (cycloalkyl) alkyl and substituted alkyl wherein the substituents are alkoxy, alkylthio and substituted amino or R ₇ and R ₈ together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl or 4-arylalkyl-1-piperazinyl, wherein the individual groups formed in this way may be substituted by alkyl, alkoxy, alkylthio, halogen or trifluoromethyl;

R ₉ and R _{10 are selected} from hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl; and η is 1, 2 or 3; characterized in that

(A) for the preparation of compounds of formula I in which R _{1 is} the meaning

R ₉ -N

Has,

(a) a thiourea of the general formula II

(II)

with an amine of general formula III

in the presence of a carbodiimide and an acid source in an organic solvent;

(b) a thiourea of the general formula VI

with monosodium cyanamide in the presence of a carbodiimide in an organic solvent; or

(c) a compound of general formula VII

with an amine of formula VIII

R ₇ R ₈ NH (VIII)

reacted in a polar solvent; or

(B) (a) for the preparation of compounds of the formula i in which R _{1 is} a radical of the formula

-N

= NCN

means

a compound of general formula IX

HKCK ^ SCH Rio H VR ₂ ^ (- Ra ^ N Λ Xp) C

(IX)

reacted with mercuric acetate in an alcoholic solvent; or

(B) for the preparation of compounds of general formula I in which R _{1 is} a radical of the formula

> = NCN

 i

ι ._

means a diamine of general formula X.

(X)

reacted with diphenyl cyanocarbonimidate in an alcoholic solvent; or

(C) for the preparation of compounds in which R _{2 has} the meaning OCO-alkyl, an alcohol of the formula I in which R _{2 is} OH, with an acid chloride of the general formula XIV

i ^(XIV >

in the presence of a base catalyst.

As already mentioned, the compounds of the invention are, for example, valuable cardiovascular agents. Preference is given to compounds having the stereochemical configuration 3S, 4R.

The term "alkyl" used in the definition of various symbols refers to straight or branched chain saturated hydrocarbon radicals having up to 8 carbon atoms and preferably from 1 to 5 carbon atoms. Similarly, the terms "alkoxy" and "alkylthio" refer to such alkyl groups attached to an oxygen or sulfur atom.

The term "alkenyl" refers to straight or branched chain hydrocarbon radicals having up to 8 carbon atoms and one double bond, preferably from 3 to 5 carbon atoms.

The term "alkynyl" refers to straight or branched chain hydrocarbon radicals having from 2 to 8 carbon atoms and a triple bond, preferably from 3 to 5 carbon atoms.

The term "cycloalkyl" refers to saturated, carbocyclic rings of from 3 to 7 carbon atoms, wherein

clopropyl, cyclopentyl and cyclohexyl are particularly preferred.

The term "halogen" refers to chlorine, bromine and fluorine atoms.

The term "halo-substituted alkyl" refers to the alkyl radicals described above in which one or more hydrogen atoms are replaced by chlorine, bromine or fluorine groups, e.g. Trifluoromethyl, with pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl and the like being preferred.

The term "aryl" refers to phenyl, 1-naphthyl, 2-naphthyl or monosubstituted phenyl, 1-naphthyl, 2-naphthyl, where the substituent is alkyl of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, Alkoxy having 1 to 4 carbon atoms, halogen, nitro, cyano, hydroxy, amino, -NH-alkyl, wherein the alkyl has 1 to 4 carbon atoms, -N (alkyl) ₂ , wherein the alkyl has 1 to 4 carbon atoms,

-CF ₃ , -OCHF ₂ , -O-CH ₂ - <"""

-S-CH ₂

(wherein R _{11 is} hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halogen, hydroxy or CF ₃ ), -O-CH ₂ -cycloalkyl or -S-CHj-cycloalkyl and disubstituted phenyl, 1-naphthyl and 2-naphthyl, wherein the substituents are selected from methyl, methoxy, methylthio, halogen, CF ₃ , nitro, amino and OCHF ₂ .

Preferred aryl radicals include unsubstituted phenyl and monosubstituted phenyl, where the substituents are

to nitro, halogen, -CF ₃ , alkyl, cyano or methoxy.

The term "heterocyclo" refers to fully saturated or unsaturated rings of 5 or 6 carbon atoms having 1 or 2 O and S atoms and / or 1 to 4 N atoms, with the proviso that the total number of heteroatoms in the ring is 4 or less. The hetero ring is linked via an available carbon atom. Preferred monocyclic hetero groups include 2- and 3-thienyl, 2- and 3-Fury I, 2-, 3- and 4-pyridyl and imidazolyl. The term "hetero" also includes bicyclic rings wherein the 5- or 6-membered ring containing 0, S and N atoms as defined above is fused to a benzene ring and the bicyclic ring is attached via an available carbon atom is. Preferred bicyclic hetero groups include 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-isoindolyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7 - or 8-isoquinolinyl, 4-, 5-, 6- or 7-benzothiazolyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5 -, 6- or 7-Benzoxadiazolyl and 4-, 5-, 6- or 7-Benzofuranzanyl.

The term "heterocyclo" also includes monocyclic and bicyclic rings in which an available carbon atom is represented by a lower alkyl radical of 1 to 4 carbon atoms, lower alkylthio radical of 1 to 4 carbon atoms, lower alkoxy radical of 1 to 4 carbon atoms, halogen, nitro, keto, cyano , Hydroxy, amino, -NH-alkyl, wherein the alkyl radical has 1 to 4 carbon atoms, -N (alkyl) ₂ , wherein the alkyl radicals have 1 to 4 carbon atoms, CF ₃ or OCHF _{2 is} substituted, or monocyclic and bicyclic rings, wherein two or three available carbon atoms have substituents selected from methyl, methoxy, methylthio, halogen, CF ₃ , nitro, hydroxy, amino and OCHF ₂ .

The term "substituted amino" refers to a radical of the formula -NZ ₁ Z ₂ , wherein Z _{1 is} hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl, and Z _{2 is} alkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl, or Z ₁ and Z ₂ together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl -l-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl which is substituted by alkyl, alkoxy, alkylthio, halogen, trifluoromethyl or hydroxy.

As already mentioned, the compounds of formula I in which R _{1 is} a radical of the formula

means, by treatment of a thiourea of the general formula II

(II)

with an amine of general formula III

(III)

ii ;. Presence of a carbodiimide, preferably 1- (3-dichloroaminopropyl) -3-ethylcarbodiimide or dicyclohexylcarbodiimide and an acid source in an organic solvent such as dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane.

The thiourea of the general formula II, in which R _{8 is} a hydrogen atom, can be prepared by heating an isothiocyanate of the general formula IV

R ₇ N = C = S (IV)

either with monosodium cyanamide or with cyanamide in the presence of an organic base such as triethylamine.

The further thiocyanates of the general formula II can be prepared according to customary methods described in the literature; see. e.g. CR Rasmussen, FJ Villani, Jr., LE Weaner, BE Reynolds, AR Hood, LR Hecker, p. 0. Nortey, A. Hanslin, MJ Costanzo, ET Powell, AJ Molinari, Synthesis (1988), p. 456 and VV Mozolis and SP Locubaitite, Russian Chemical Reviews, Vol. 42 (1973), p. 587.

The aminoalcohol of the general formula III in which R _{2 represents} a hydroxyl group can be prepared by methods described in the literature; see. JM Evans, CS Fake, TC Hamilton, RH Poyser, EA Watts, J.Med.Chem., Vol. 26 (1983), p. 1582 and J.Med.Chem., Vol. 29 (1986), p. 2194; RW Lang, PF Wenk, Helvetica Chimica Acta, Vol. 71 (1988), p. 596; EP-A2 0205292 (1986) and WO 87/07607.

The amine of general formula III, in which R _{2 is} hydrogen, lä / 3t from ketone of the general formula V

produce by conventional methods. The ketone of general formula V can be obtained by methods known from the literature; see. e.g. P. Sebok and T. Timar, Heterocycles, Vol. 27 (1988), p. 2595; P. Teixidor et al., Heterocycles, Vol. 27 (1988), p. 2459; A. Benerji and N. C Goomer, Tetrahedron Letters, (1979), p. 3685; G. Ariamala and K.K. Subramanian, Tetrahedron Letters, Vol. 29, No. 28 (1988), s. 3487 to 3488.

The compounds of the general formula I in which R _{1 is} a radical of the formula

XJ *

Vncn

R ₉ -ν '

can also be prepared by reacting a thiourea of the general formula VI

(VI)

with monosodium cyanamide in the presence of a carbodiimide, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or dicyclohexylcarbodiimide, in an organic solvent.

The compounds of the formula VI can be prepared from the aminoalcohol of the formula III by customary processes (cf the abovementioned Rasmussen and Mozolis references).

The compounds of the general formula I in which R _{1 is} a radical of the formula

Vncn

R ₉ V

can also be prepared by reacting a compound of general formula VII

V = NCN

R ₉ -N

(VII)

with an amine of general formula VIII

R ₇ R ₈ NH

(VIII)

in a polar solvent such as isopropanol. The compounds of the general formula VII are prepared by reacting an amine of the general formula III with diphenyl cyanocarbonimidate.

The compounds of general formula I _f in the R, a radical of the formula

fö

^F n

-N

= NCN

can be prepared by reacting a compound of general formula IX

Ζ91Ϊ15

Ί O

^ SCH ₃

ln

! Xp

-R ₂

(IX)

reacted with mercury (II) acetate in an alcoholic solvent such as methanol.

The compounds of general formula IX are prepared by reacting a diamine of general formula X.

R ₈

NH

NH

(X)

with dimethyl-N-cyanodithioiminocarbonate.

The compounds of the general formula i in which R _{1 is} a radical of the formula

> = NCN

can also be prepared by treating a diamine of general formula X with diphenyl cyanocarbonimidate in an alcoholic solvent such as 2-propanol.

The compound of the general formula X in which R _{2 is} trans-hydroxyl is obtained by reacting an epoxide of the general formula XI

with a diamine of the general formula XIi

ρ (XII)

Rio

in an alcoholic solvent, such as ethanol.

The preparation of the epoxide of the general formula Xi is described by Evans and Lang (cf the above references).

The compounds of the general formula χ can also be prepared from the aminoalcohol of the general formula I and an alkylating agent of the general formula XIIi

(XIII)

in the P is a protective group and X is an leaving group, such as Cl, Br and J, in the presence of a base catalysis

sators with subsequent deprotection. Compounds of general formula X can also be prepared from a ketone or an aldehyde of general formula XIII (i.e., X is oxo) and an aminoalcohol of general formula III by conventional reductive amination procedures, followed by removal of the protecting group P.

The compounds of the invention in which R _{2 has} the meaning OCO-alkyl can be obtained by acylation of the alcohol of the formula I in which R _{2 has} the meaning OH, with an acid chloride of the general formula XIV

^A alkyl

(XIV)

in the presence of a base catalyst such as pyridine or triethylamine.

For the preparation of the individual enantiomers of the compounds of the formula τ (wherein R ₂ = H, OH) is a compound of general formula III (R ₂ = H, OH) to diastereomeric amides of the general formulas XV and XVI

(XV)

(XVI)

29 I3 </ 715

reacted by treatment with chiral, non-racemic mandelic acid in the presence of dicyclohexylcarbodiimide.

The compounds of general formula XV and XVI are separated by crystallization or chromatography. The enantiomer of mandelic acid yielding crystalline diastereomer having the desired 4R stereochemistry of benzopyran (as shown in the general formula XV) is preferred in the separation step.

The compounds of general formulas XV and XVI are then hydrolyzed by heating in the presence of sulfuric acid in dioxane to give the enantiomers of general formulas XVII and XVIII

NH ₂

(XVII) (XVIII)

The enantiomers of the general formulas XVII and XVIII are then converted to the chiral, non-racemic compounds of the general formula I.

The compounds of the invention may have asymmetric centers on the carbon atoms 2-4 of the benzopyran ring. Any of the radicals R may also have an asymmetric carbon atom. As a result, the compounds of general formula I may exist in diastereomeric forms or in the form of mixtures thereof. In the process described above, starting materials, racemates, enantiomers or diastereomers can be used. In the preparation of diastereomeric products can be

separating them by conventional chromatography or fractional crystallization techniques.

The compounds of the invention wherein R ₉ and / or R _{8 is} hydrogen may be present as a mixture of tautomers of the structures shown below. The tautomeric products are obtained in relative proportions that differ from compound to compound. All forms fall within the scope of general formula 1.

R ₇ R ₈

= Ncn

R ₉ -N

R

n:

R ₈

WNHCN

NHCN

31 19 ^ 775

The compounds of formula I and the pharmaceutically acceptable salts thereof act as potassium channel activators. Thus, the compounds of the invention are useful as antiarrhythmic agents, anti-ischemic agents and in the treatment of hypertension.

It has been found that compounds of the general formula I in which R _{7 is} aryl, arylalkyl, cycloalkyl, (cycloalkyl) -alkyl, heterocyclo or (heterocyclo) -alkyl are preferred as anti-ischemic active substances, ie for the treatment of ischemic conditions, such as myocardial ischemia, cerebral ischemia, ischemia of the lower limbs and the like. Especially preferred are such compounds in which R _{7 is} aryl or arylalkyl and R ₈ and R _{9 are} each hydrogen. Although any compounds of general formula I can be used as anti-ischemic agents, it has been found that these preferred anti-ischemic agents have little or no vasodilator activity. This means that there is less likelihood of coronary withdrawal, marked negative pressure and coronary underperfusion in these compounds.

Similarly, particularly preferred compounds of general formula I for reducing high pressure are those compounds in which R _{7 is} hydrogen or alkyl of 1 to 3 carbon atoms, R ₇ and R ₈ together with the nitrogen atom to which they are attached are a 5- or 6-membered ring, such as pyrrolidine or piperidine, R _g and R _{10 are} each hydrogen and η is 1 or 2.

Thus, for example, by administering a composition containing one (or a combination of several) of the compounds of the invention, an ischemic condition of a mammal (e.g., human) is diminished. A single dose, or preferably 2 to 4 divided daily doses, provided on the basis of about 0.001 to 100 mg per kg body weight per day, and preferably from about 0.1 to about 25 mg per kg per day, are useful for reducing ischemic state. The active ingredient is preferably administered orally, but parenteral routes of administration, such as a subcutaneous, intramuscular or intravenous route of administration, or any other delivery pertinent, such as inhalation or intranasal solutions or transdermal bandages, may be used. The above dosages are also useful for other cardiovascular (e.g., hypertension) and non-cardiovascular uses.

As a result of the potassium channel activating action of the compounds of the invention, these compounds are also useful in the treatment of cardiovascular disorders and any disorders associated with smooth muscle contraction. For example, the compounds of the invention are useful in the treatment of congestive heart failure, peripheral vascular disorders (eg, Raynaud's disease), pulmonary hypertension, antianginal agents, antifibrillatory agents, thrombolytic agents, and myocardial infarct limitation ,

The compounds of the invention are also useful in the treatment of central nervous system disorders (eg, Parkinsonism, antitremor agents, epilepsy), renal failure therapy, bladder incontinence therapy, antidiarrheal drugs, preeclampsia, dysmenorrhea, and preterm labor and to promote hair growth (eg in the treatment of

33 zs </ 15

male bald patches) and expected as antiasthmatic agents.

The compounds of the invention may also be formulated in combination with a diuretic such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide or benzthiazide as well as ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and Spironolactone and salts of such compounds, angiotensin converting enzyme inhibitors such as captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril and salts of such compounds, thrombolytic agents such as tissue plasminogen Activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase and anisoylated plasminogen streptokinase activator complex (APSAC, Eminase, Beecham Laboratories) or calcium channel blockers such as nifedipine and diltiazem. For such combination products, in the form of a solid dose, the compounds of the invention are employed within the dose range described above and the remaining pharmaceutically active agents within their recognized dose range.

The compounds of general formula I and combinations thereof may be formulated in the manner described above in the form of compositions such as tablets, capsules or elixirs for oral administration, and in the form of sterile solutions or suspensions for parenteral administration. They may also be administered via transdermal bandages or nasal inhalation solutions. About 10 to 500 mg of a compound of formula I is processed with a physiologically acceptable carrier, diluent, excipient, preservative, stabilizer, flavoring and the like in a unit dosage form as recognized by accepted pharmaceutical practice. The

34 ZSQ Ϊ75

Amount of the active ingredient in such compositions or preparations is such as to provide a suitable dosage in the specified range.

Preferred compounds are those in which a is nitrogen or -CR ₅ ; b and c are each -CH-; R ₁ a remainder of the formula?

V ⁸

R ₉ -N

^ = NCN or

^r n

 = NCN;

means;

R _{2 is} hydroxy; R ₃ and R _{4 are} each alkyl; R _{5 represents} an electron-withdrawing group; R _{6 is} hydrogen, alkyl, O-alkyl or amino; R _{7 is} hydrogen, alkyl, aryl or arylalkyl, R _{8 is} hydrogen; R _{9 is} hydrogen or alkyl; R _{10 is} hydrogen; and η is 1 or 2.

Particularly preferred are compounds in which a is nitrogen or -CR ₅ ; b and c are each -CH-; R _{2 is} trans-hydroxy; R ₃ and R _{4 are} each methyl; R _{5 is} -CN or -NO ₂ ; R _{6 is} hydrogen; R _{7 is} methyl, ethyl, phenyl or phenylmethyl; R _{8 is} hydrogen; Rg is hydrogen; R _{10 is} hydrogen; and η is 1.

A particularly preferred compound of the invention, which is used in particular as c: isiischemic agent, is

Aoi -fuhr uuc, b I) tisple.It

Specific embodiments of the invention are described in the following examples.

example 1

(trans) -N "-cyano-N- (6-cyano-3/4-dihydro-3-fcydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - (1,1 -dijnethylpropyl) guanidine

A. N -cyano-N'-Ufl-dimethylpropyl) thiourea

A suspension of monosodium cyanamide (0.64 g, 10 mmol) in absolute ethanol (30 mL) was slowly added at room temperature with 1,1-dimethylpropyl isothiocyanate (1.29 g, 10 mmol). During the addition an exothermic reaction took place, and towards the end of the addition, a homogeneous solution formed from the original heterogeneous mixture. The mixture was stirred for 2 hours at room temperature and then heated for 1 hour at 75 ⁰ C then the reaction mixture was cooled to room temperature and the solid was filtered off. The filtrate solution was evaporated. The title compound A (1.6 g) was obtained as a colorless solid.

B. (trans) -N ^M -Cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -Ν » - (1, l-dimethylpropyl) -guanidine

A solution of the title compound A (0.94 g, 5.5 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (manufactured according to Evans et al., J. Med. Chem., Vol. 26 (1983), page 1582 and J. Med. Chem., Vol. 29 (1986), page 2194) (1.0 g, 4, 6 mmol) in dimethylformamide (5 ml) was added under argon at room temperature with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.14 g, 5.9 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1 N HCl and ethyl acetate. The organic phase was separated and the aqueous phase reextracted with ethyl acetate. The combined organic phase was washed with water, aqueous sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the filtrate was evaporated. The residue was purified by flash chromatography on silica gel (1: 1 hexane / EtOAc). The fractions containing the desired product were combined and evaporated. A colorless solid (620 mg) was obtained. This solid was triturated with isopropyl ether. The title compound was obtained from mp 207 to 208 ^° C.

C ₁₉ H ₂₅ N ₅ O ₂ : CH N

Calc .: 64.20 7.09 19.71 F .: 64.04 7.11 19.44

Example 2

(trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-feenzopyran-4-yl) -N ¹ -ethylguanidine

A. N-cyano-N · ethylthiourea

37 19 ^ 7-75

A suspension of monosodium cyanamide (6.4 g, 100 mmol) in absolute ethanol (30 mL) was slowly replaced with ethyl isothiocyanate (9.0 mL, 100 mmol) with stirring at room temperature. During the addition, an exothermic reaction took place, and towards the end of the addition, a homogeneous solution was formed from the reaction mixture. The mixture was stirred for 2 hours at room temperature and then heated for 1 hour at 75 ⁰ C and then the reaction mixture was cooled to room temperature. The insoluble material was filtered off, 700 mg). The mother liquor was evaporated and the resulting solid triturated with isopropanol-isopropyl ether. The title compound A (11.2 g) of mp> 240 ° C was obtained.

B. (trans) -N ^H-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-4-yl) -N ¹ -ethylguanidin

A solution of the title compound A (1.15 g, 8.9 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (manufactured according to Evans et al., J. Med., ex., Vol. 26 (1983), page 1582 and J. Med., ex., 29 (1986), page 2194) (1.5 g, 6, 9 mmol) in dimethylformamide (5 ml) was added under argon at room temperature with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.71 g, 8.9 mmol). The mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1 N HCl and ethyl acetate. The organic phase was separated and the aqueous phase reextracted with ethyl acetate. The combined organic phase was washed with water, aqueous sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by flash chromatography on silica gel (25% acetone in dichloromethane). The fractions containing the desired product were combined and evaporated. A colorless solid (801 mg) was obtained. This solid product was recrystallized from acetonitrile-ether. The title compound, mp 185-188 ⁰ C.

^C 16 ^H 19 ^N 5 ° 2 • 0.2 H ₂ O: C H 17 22 N calc .: 60.64 6 16 22 10 gef. : 60.63 6 25 example 3

(trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ -phenylguanidine

A. N-cyano-N-phenyi thiourea

A suspension of mononatriuracyanamide (6.4g, 100mmol) in absolute ethanol (170ml) was added slowly with phenylisothiocyanate (12.5ml, 104.5mmol) with stirring at room temperature. The reaction mixture was stirred for 1 hour at room temperature and then heated to 75 ⁰ C for 4 hours. Subsequently, the reaction mixture was cooled to room temperature and the colorless solid was filtered off and washed with ethanol. The title compound A (13.6 g) of mp> 250 ° C was obtained.

B. (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ -phenylguanidine

A solution of the title compound A (1.06 g, 5.96 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (manufactured according to Evans et al., J. Med., ed., Vol. 26 (1983), page 1582 and J. Med., ex., 29 (1986), page 2194) (1.0 g, 4, 59 mmol) in dimethylformamide (5 ml) was added at room temperature under argon with 1- (3-dimethyl-1-aminopropyl) -2-ethylcarbodiimide hydrochloride (1.17 g, 5.96 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1 N HCl and ethyl acetate. The organic phase was separated and the aqueous phase reextracted with ethyl acetate. The combined organic phase was washed with water, aqueous sodium bicarbonate solution and brine.

39 /.SV? 15

to wash. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the colorless residue was triturated with ether. The title compound was obtained (1.3 g), mp 247-249 ° C. (with foaming).

^C 20 ^H 19 ^N 5 ° 2 ^: CHN

Calculated: 66.46 5.30 19.38 Found: 66.09 5.30 19.35.

Example 4

(trans) -N "-cyano-N- (3 _/ 4-dihydroxy-3-hydroxy-2 _/ 2-dimethyl-6-nitro-2H-1-benzopyran-4-yl) -N'-ethylguanidine

A solution of the title compound A of Example 2 (1.2 g, 9.4 mmol) and (trans) -4-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran ( 1.5 g, 6.3 mmol), prepared according to Evans et al., J. Med. Chem., Vol. 26 (1983), page 1582 and J. Med., Ex., 29 (1986), page 2194), in dimethylformamide (5 ml) at room temperature under argon was added 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (2.1 g, 10.7 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1 N HCl and ethyl acetate. The organic phase was recovered and the aqueous phase reextracted with ethyl acetate and the combined organic phase washed with water, aqueous sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (hexane / acetone = 6: 4). A colorless solid (500 mg) was obtained. This solid was triturated with isopropyl ether. The title compound, mp 204-205 ⁰ C.

C ₁₅ H ₁₉ N ₅ O ₄ 0.17 H ₂ O: CH N

Calculated: 53.55 5.79 20.82 Found: 53.89 5.63 20.48.

⁴⁰ ZS9? 7S

Example 5

(trans) -3,4-dihydro-3-hydroxy-2,2-dimethyl-4- [2- (cyanoimino) -l-pyrrolidinyl] H-l-benzopyran-e-carbonitrile

A. (trans) -4 - [(2-aminoethyl) amino] -3 _/ 4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile

A suspension of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-di-ethyl-2H-benzopyran (1.2 g, 5.97 mmol) (prepared according to Evans et al., J. Med Chem., Vol. 29 (1986), page 2194) in ethanol (7.0 ml) was washed at room temperature with ethylenediamine (2.4 ml, 35.8 mmol). The reaction mixture was stirred at room temperature for 36 hours. The solvent was then removed under reduced pressure, the residue was further dried using a vacuum pump. The title compound A (1.74 g,> 100%) was obtained as a colorless foam. This material was used without purification for the next reaction.

B. (trans) -3,4-dihydro-3-hydroxy-2,2-dimethyl-4- [2- (cyanoimino) -l-pyrrolidinyl] -2H-1-benzopyran-6-carbonitrile

A solution of the title compound A (1.74 g, 5.97 mmol) in ethanol was triethylamine (1.7 mL, 11.94 mmol) at room temperature followed slowly by dimethyl N-cyanodithioiminocarbonate (1.16 g, 11 , 94 mmol with 90%). The reaction mixture was heated for 3 hours at 8O ⁰ C and then cooled to ambient temperature. The solvent was evaporated. A pale yellow foam (2.4 g) was obtained. This material was taken up in methanol (20 ml). The resulting suspension was treated with mercuric acetate (2.52 g, 7.77 mmol). The reaction mixture was stirred for 2 hours at room temperature and the solvent was evaporated under reduced pressure. The residue

was diluted with water, basified with 5 N NaOH to pH -9.0 and the product extracted with 5% methanolic chloroform. The combined organic extracts were washed with brine to give a thick emulsion. The biphasic gel was filtered through a celite pad. The organic phase was separated and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (5% methanol in chloroform) on silica gel to give a colorless residue. This residue was triturated with ethyl acetate. The desired product was obtained (740 mg). The mother liquor was evaporated and triturated with ethyl acetate. A second crop (370 mg) was obtained, giving an overall yield of 1.1 g. The combined material was recrystallized from hot ethyl acetate. The title compound was obtained as a white powder of mp 254-255 ⁰ C.

C ₁₆ H ₁₇ N ₅ O ₂ «0.42 H ₂ O: CH N

Calculated: 60.27 5.63 21.97 Found: 60.40 5.30 21.84

Example 6

(trans) -N "-cyano-N- (3 _/ 4-dihydro-3-hydroxy-2 _/ 2-dimethyl-2H-pyrano [3,2-c] pyridin-4-yl) -phenylguanidine

A solution of the title compound A of Example 3 (2.2 g, 12.5 mmol) and (trans) -4-amino-3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol (1.1 g, 5.7 mmol) (prepared according to EP 0 205 292 A2) in dimethylformamide (5 ml) was purified under argon at room temperature with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (2.2 g, 10.8 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with water (pH 11) and ethyl acetate. The organic phase was separated and the aqueous phase reextracted with ethyl acetate. The combined organic phase was washed with water,

42 ZS ^ JI 5

aqueous sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (acetone: dichloromethane = 1: 4). A colorless solid (470 mg), which was crystallized from acetonitrile to give the title compound, melting at 233-236 ⁰ C was obtained.

^C 18 ^H 19 ^N 5 ° 2 ^: CHN

Calc .: 64.08 5.67 20.76 F .: 63.88 5.48 20.76.

Example 7

(trans) -N ^l-cyano-N- _{(6-cyano-3/4-dihydro-3-hydroxy-2/2-dimethyl-2H-l-benzopyran-4-yl)} -l-pyrrolidinecarboximidamide

A. (trans) -4 - [[(cyanoimino) phenoxymethyl] amino] -3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile

A solution of (trans) -4-AmInO-S, 4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chem. 26 (1983), page 1582 and J. Med. Chem., 29 (1986), page 2194) (5.0 g, 23 mmol) in isopropanol (50 mL) was treated at room temperature with diphenyl cyanocarbonimidate (5 , 5 g, 25 mmol). The reaction mixture was allowed to stir at room temperature for 16 hours. Then most of the isopropanol was evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed successively with 10% citric acid, ι η sodium hydroxide solution and brine. It was then dried over anhydrous magnesium sulfate, evaporated and the residue crystallized from chloroform-isopropyl ether. The title compound A (4.2 g) was obtained as a colorless solid of mp 186-188 ⁰ C.

C ₂₀ H ₁₈ N ₄ O ₃ -O, 6H ₂ O: CHN

Calculated: 64.37 5.18 15,02 Found: 64.64 4.86 14.75

B. (trans) -N'-cyano-N- (6-cyano-3 _/ 4-dihydro-3-hydroxy-2 _/ 2-dimethyl-2H-1-benzopyran-4-yl) -l-pyrrolidine-carboximidamide

To a solution of title compound A (0.8 g, 12.2 mmol) in isopropanol (4 mL) was added pyrrolidine (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The suspension was diluted with ether. The colorless solid was filtered off. The title compound (0.4 g) was obtained, melting at 263-264 ⁰ C. ^C 18 ^H 21 ^N 5 ° 2 CHN calc .: 63.70 6.24 20.64 63.45 6.29 Found .: 20 , 88th

Example 8

(trans) -N "-cyano-N- (e-cyano-3,4-dihydro-3-hydroxy-2 _/ 2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ -ethyl-N- methylguanidine

A. (trans) -N'-Cyano-N- (6-cyano-3 _/ "-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-4-yl) -N-methylcarbamidinsäurephenylester

A solution of (trans) -S ^ 4- (methylamino) -2H-i-benzopyran-6-carbonitrile (prepared according to Evans et al., J.Med.Med., Vol. 26 (1983), page 1582 and US Pat J. Med. Chem., Vol. 29 (1986), page 2194) (1.0 g, 4.3 mmol) in isopropanol (4 mL) at room temperature with diphenyl cyanocarbonimidate (1.0 g, 4.3 mmol). added. The reaction mixture was stirred at room temperature for 16 hours. Then most of the isopropanol was evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed successively with 10% citric acid, 1N sodium hydroxide solution and brine. It was then dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography (ethyl acetate: hexanes 1: 1) on silica gel. you

obtained the title compound A. This compound was used without further purification for the next step.

B. (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ -ethyl- N-raethylguanidin

To a solution of the title compound A (0.1 g, 0.27 mmol) in isopropanol (1 mL) and triethylamine (0.25 mL) was added ethylenealc hydrochloride (0.1 g, 1.2 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. Then most of the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed successively with 10% citric acid, aqueous sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was triturated with ether. The title compound was obtained as a colorless solid, mp 227-228 ⁰ C.

Example 9

(trans) -N "-cyano-Ν- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - [2- (dimethylamino) -ethyl] -guanidine

A suspension of the compound of Example 7, Section A (0.8 g, 2.2 mmol) in isopropanol (3 mL) was washed at room temperature with 95% 1,1-dimethylethylenediamine (0.5 g, 5.7 mmol ). The solution was stirred at room temperature for 20 hours and evaporated under reduced pressure. The residue was triturated with isopropyl ether. The title compound (0.4 g were obtained as a white solid, mp 172-173 ⁰ C.

¹ H NMR _(CDCl3) 6 7.6 (s, 1 H), 7.4 (dd, J = 2.0 & 9.0 Hz, IH), 6.9 (d, J = 9.0 Hz , 1 H), 6.6 (s, 1 H), 4.9 (t, J = 9.0 HZ, 2 H), 3.5 (d, J = 9.0 HZ, 1 H), 3 , 4 (S, 2H), 2.5 (m, 2H), 2.0 (S, 6H), 1.5 (S, 3H), 1.3 (s, 3H); ¹³ C NMR

(CDCl ₃ ) S 163.4, 156.8, 133.1, 132.5, 122.8, 118.8, 118.7, 118.0, 103.9, 80.4, 76.2, 69 , 1, 60.8, 51.8, 44.6, 41.7, 26.4, 18.5; IR (KBr) 1126.9, 1267.0, 1431.4, 1489.0, 1577.0, 1635.8, 2173.3, 3391.9, 3407.6 cm ^-1 .

^C 18 ^H 24 ^N 6 ° 2 60 C H 10 23 N About: 60 65 6.79 23 , 58 Found .: , 53; 6.75 , 62nd example

(trans) -N'-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ -methylguanidine

To a suspension of the compound of Example 7, Section A (1.0 g, 2.8 mmol) in isopropanol (6 mL) at room temperature was added methylamine (40% solution in methanol, 1 mL). The reaction mixture was stirred for 20 hours at room temperature and then evaporated under reduced pressure. The resulting crude product was crystallized from isopropanol. The title compound (0.4 g) was obtained as a white solid, mp 212-214 ⁰ C.

¹ H NMR (CDCl 3 / DMSO) S 7.5 (S, 1 H), 7.45 (d, J = 9.0 Hz, 1 H), 6.9 (m, 2 H), 6.8 ( d, J = 8.0 Hz, 1H), 5.55 (br, IH), 4.85 (br, 1H), 3.7 (m, 1H), 2.88 (d, J = 5.0Hz, 3H), 1.48 (S, 3H), 1.24 (s, 3H); ¹³ C NMR (CDCl3 / DMSO) 160.5, 155.5, 131.6, 131.3, 123.7, 117.9, 117.3, 116.9, 102.2, 79.4, 76, 6, 70.9, 27.6, 25.6, 17.7; IR (KBr) 1267, 1419, 1489, 1576, 1608, 2170, 2225, 2977, 3338 cm ^-1

C ₁₅ H ₁₇ N ₅ O ₂ 0.3H ₂ O: CHN

Calc .: 59.16 5.82 23.01

F .: 59.16 5.57 23.01.

46 JfV? / 5

Example-11

(trans) -4 - [(cyanoimino) [[4- (phenylmethyl) -1-piperazinyl] methyl] amino] -3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran -6-carbonitrile

To a suspension of the compound of Example 7, Section A (2.0 g, 5.5 mmol) in isopropanol (5 mL) was added 4- (phenylmethyl) -1-piperazine (1.0 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature and evaporated under reduced pressure. The resulting crude product was purified by riash chromatography on silica gel eluting with dichloromethane / acetone (7/3). The title compound (0.6 g) was obtained. This compound was recrystallized from isopropanol-ether. The desired product (250 mg) was obtained as a white solid, mp 205-207 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 7.4 (s, 1 H), 7.3 (d, J = 8.0 Hz, 1 H), 7.2 (d, J = 8.0 Hz, 1 H), 7.0 (s, 6 H), 6.6 (d, J = 9.0 Hz, 1 H), 5.6 (d, J = 6.0 Hz, 1 H), 4, 6 (t, J = 8.0 & 10.0 Hz, 1H), 3.2 (m, 5H), 2.2 (m, 5H), 1.14 (s, 3H), 0 , 88 (s, 3H); ¹³ C NMR (DMSO-d ₆ ) 161.1, 156.4, 137.6, 133.1, 132.9, 129.1, 128.3, 127.2, 124.6, 117.9, 102 , 7, 80.6, 71.5, 61.9, 53.0, 52.2, 46.6, 26.7, 18.6; IR (KBr) 1125, 1490, 1524, 1577, 1611, 2170, 2224, 3429 cm ^-1 .

^C 25 ^H 28 ^N 6 ° 2 ^: CHN

Calculated: 67.54 6.35 18.91 Found: 67.29 6.37 18.73.

Example 12

(trans) -W-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -guanidine

To a suspension of the compound of Example 7, Section A (1.0 g, 2.8 mmol) in isopropanol (6 mL) was added ammonium hydroxide (1 mL) at room temperature. Then it was 20

Stirred for hours at room temperature and evaporated under reduced pressure. The resulting crude product was crystallized from acetone / Ess.vgsäureethylester. The Ti-.telveroindung (0.31 g) was obtained as a white solid, mp 250-251 ⁰ C.

¹ H NMR (DMSO-d ₆ ) S 7.7 (dd, J = 2.0 & 7.0 Hz, IH), 7.5 (s, 1 H), 6.9 (m, 2 H), 7.0 (d, J = 9.0 Hz, 1H), 5.8 (brs, 1H), 4.8 (brs, 1H), 3.6 (m, 1H), 1 , 48 (s, 3H), 1.25 (s, 3H); ¹³ C NMR (DMSO-d ₆ ) 162.3, 156.3, 132.9, 132.6, 124.8, 119.1, 118.1, 102.7, 80.5, 71.3, 26 , 5, 19.0; IR (KBr) 1064, 1268, 1489.7, 1555, 1635, 2183, 2225, 3432 cm ^-1

C ₁₄ H ₁₅ N ₅ O ₂ : CHN

calculated: 58.93 5.30 24.55

Found: 58.74 5.32 24.23.

Example 13

(trans) -N "-cyano-Ν- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - (methylethyl) - · janidin

To a suspension of the compound of Example 7, Section A (2.0 g, 5.5 mmol) in isopropanol (5 ml) was added isopropylamine (1.5 ml) at room temperature. It was then stirred for 20 hours at room temperature and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel eluting with 7/3 dichloromethane / acetone. The title compound (1.2 g) was obtained. This solid was crystallized from isopropanol-isopropyl ether. The desired product was obtained as a white solid, mp 150-152 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 7.6 (dd, J = 2.0 & 7.0 Hz, 1 H), 7.5 (S, 1 H), 7.2 (d, J = 9 , 0 Hz, 1 H), 7.0 (d, J = 9.0 Hz, 1 H), 6.8 (d, J = 8.0 Hz, 1 H), 5.9 (d, J = 5.0 Hz, 1H), 4.8 (t, J = 9.0 Hz, 1H), 3.9 (m, 1H), .V., 8 (m, IH), 1.47 (s, 3H), 1.24 (s, 3H), 1.2 (d, J = 3.0Hz, 6H); ¹³ C NMR (DMSO-dg) 159.5, 156.3, 132.7, 132.4, 125.2, 119.1, 118.0, 117.8,

102.7, 80.5, 71.1, 51.5, 43.4, 26.7, 22.6, 22.4, 18.7; IR (KBr) 1268, 1490, 1587.8, 2170, 2226, 2978, 3419 cm ^-1

C ₁₇ H ₂₁ N ₅ O ₂ -O ₁ IH ₂ O: CHN

Calc .: 62.03 6.49 21.28

F .: 61.75 6.66 21.86.

Example 14

(trans) -N ^M cyano-N- (6-cyano-3 _f 4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-4-yl) -N ¹ -dimethylguanidin

A suspension of the compound of Example 7, Section A (1.0 g, 2.8 mmol) in isopropanol (6 mL) was washed at room temperature with dimethylamine hydrochloride (0.33 g, 4.2 mmol) and then with powdered potassium carbonate (0.57 g, 4.2 mmol). The reaction mixture was stirred at room temperature for 20 hours and evaporated under reduced pressure. The residue was dissolved in chloroform (150 ml), washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The resulting crude product was crystallized from dichloromethane-ether. The title compound (0.44 g) was obtained as a white solid. This solid was recrystallized from acetonitrile-chloroform. This gave a colorless solid of mp 196-197 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 7.7 (S, IH), 7.6 (dd, J = 3.0 & 8.0 Hz, 1 H), 7.2 (d, J = 9, 0 Hz, 1 H), 6.9 (d, J = 9.0 Hz, 1 H), 5.8 (d, J = 6.0 HZ, 1 H), 4.9 (t, J = 9 , 0 & 10.0 Hz, 1 H), 3.6 (dd, J = 8.0 & 5.0 Hz, 1 H), 3.0 (S, 6 H), 1.42 (s, 3 H), 1.24 (s, 3H); ¹³ CNMR (DMSO-dg) 159.3, 154.9, 131.5, 130.8, 123.4, 116.1, 101.4, 78.9, 70.3, 51.5, 25.2 , 17.0; IR (KBr) 1143, 1269, 1398, 1489, 1527, 1595, 2168, 2226, 2935, 2980, 3433 cm ^-1 .

^C 16 ^H 19 ^N 5 ° 2 · ⁰ ' ^{5 H} 2 ^0: calc .:

Found .:

C 6 H 21 N 59 , 61 5 25 22 , 73 59 , 44 95 , 03.

Example 15

(trans) -N "-cyano-Ν- (" S -cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N "^1" -phenylmethylguanidine

A suspension of the compound of Example 7, Section A (0.5 g, 1.4 mmol) in isopropanol (3 mL) was added benzylamine (90%, 0.5 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature and then evaporated under reduced pressure. The residue was combined with another batch of the same material and eluted by flash chromatography on silica gel eluting with hexane-ethyl acetate (3: 7). A white solid (0.8 j) was obtained . This solid was recrystallized from acetonitrile-isopropyl ether. The title compound was obtained as a colorless solid of mp 188-189 ° C.

¹ H NMR (CDCl ₃ ) 6 7.7 (m, 1H), 7.5 (dd, J = 2.0 & 9.0 Hz, 1H), 7.4 (m, 6H), 6 , 86 (d, J = 9.0 Hz, 1H), 5.8 (s, 1H), 4.8 (m, 1H), 4.5 (d, J = 5.0 Hz, 2 H), 3.7 (dd, J = 6.0 & 4.0 Hz, 1H), 1.41 (s, 3H), 1.19 (s, 3H); ¹³ C NMR (CDCl ₃ ) 158.7, 154.5, 136.8, 130.7, 126.5, 125.2, 125.0, 123.0, 116.0, 101.0, 78.6 , 42.6, 24.8, 16.9; IR (KBr) 1267, 1491, 1579, 1595, 2175, 2222, 3433 cm ^-1 .

^C 21 ^H 21 ^N 5 ° 2 ^: 67 C H 18 N calc .: 67 , 18 5.64 18 , 66 Found .: , 14 5.55 16 , 65th example

(trans) -N ^n-cyano-N- (6-oyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-4-yl) -N ¹ - [2- [ (phenylmethyl) -methylamine] -ethyl] -guanidine

To a suspension of the compound of Example 7, Section A (0.5 g, 1.4 mmol) in isopropanol (3 mL) at room temperature was added N-methylbenzylethylamine (0.5 mL). The Re-

so

The reaction mixture was stirred for 24 hours at room temperature. From the initially heterogeneous mixture slowly a homogeneous solution was formed. As the reaction progressed, the product precipitated out of the reaction mixture. After completion of the reaction, the solid was filtered off and triturated with ether. The title compound (0.45 g) was obtained as a colorless solid, mp 184-185 ⁰ C.

¹ H NMR _(CDCl3) S 9.4 (s, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.2 (m, 4 H), 6.96 (S , 2H), 6.87 (d, J = 9.0 Hz, IH), 6.4 (S, 1H), 4.9 (m, 2H), 3.4 (m, 4H) , 2.6 (m, 2H), 2.1 (s, 3H), 1.49 (S, 3H), 1.26 (s, 3H); ¹³ C NMR (CDCl ₃ ) 205.2, 160.7, 155.6, 131.6, 128.0, 127.4, 126.2, 123.5, 118.0, 117.3, 117.1 , 102.4, 79.4, 61.3, 55.6, 40.5, 25.7, 17.74; IR (KBr) 1126, 1267, 1489, 1575, 1608, 2172, 2224, 2800, 2976, 3421 cm ^-1 .

^C 24 ^H 28 ^N 6 ° 2 ^: calc .:

Found .:

C H N 43 66 , 64 6.52 19 99th 66 40 6.52 19 example 17

(trans) -N'-cyano-N- (6-cyano-3 , A -dihydro-3-hydroxy-2, -dimethyl-2H-1-benzopyran-4-yl) -N ¹ - (2-methoxyethyl ) guanidine

A suspension of the compound of Example 7, Section A (0.5 g, 1.4 mmol) in isopropanol (3 mL) was treated at room temperature with 2-methoxyethylamine (0.12 g, 1.7 mmol, 0.15 mL). added. The reaction mixture was stirred for 20 hours at room temperature and then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate. The title compound (0.3 g) was obtained as a colorless solid, melting at 94-96 ⁰ C.

¹ H NMR (CDCl ₃ ) S 7.5 (s, 1H), 7.38 (d, J = 7.0 Hz, 1H), 6.8 (m, 3H), 4.86 (s , 1H), 4.0 (m, 1H), 3.5 (m, 4H), 3.2 (S, 3H), 1.9 (S, 1H), 1.43 (s , 3H), 1.19 (s, 3H); ¹³ C NMR (CDCl ₃ ) 162.6, 156.8, 133.2, 132.4, 122.5, 119.0, 118.5,

118.1, 103.9, 80.2, 74.7, 60.3, 58.9, 52.2, 26.4, 21.0,

18,7, 14,1; IR (KBr) 1635, 1693, 3404 cm " ¹ .

C ₁₇ H ₂₁ N ₅ O ₃ -O, 24H ₂ O: CHN

Calculated: 58,71 6.23 20.14

Found: 58.81 6.38 20.04.

Example 18

(3S-trans) -N "-cyano-Ν- (6-cyano-3,4-dihydro-S-hydroxy, 2-dimethyl-2H-1-benzopyran-4-yl) -N ·-phenylguanidine

A. [3R- [3ct, 4β (S *)]] - N - (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) - ot-hydroxybenzeneacetamide

[38- [3α, 4β (R *)]] - N - (6-cyano-3,4-dihydro-3-hydroxy-1,2-dimethyl-2H-i-benzopyran-4-yl) -a- hydroxybenzeneacetamide

A solution of (trans) M-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med., Ex., Vol. 26 (1983), page 1582 and J. Med. Chem. 29 (1986), page 2194) (10.0 g, 45.9 mmol), S - (+) - mandelic acid (6.98 g, 45.9 mmol) and hydroxybenzotriazole hydrate (6.2 g , 45.9 mmol) in dimethylformamide (60 ml) was added at ⁰ ° C with dicyclohexylcarbodiimide (9.5 g, 45.9 mmol). It was then stirred for 20 hours at room terature and then cooled in an ice bath. The precipitated solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in 5% methanol in chloroform and washed with 1 N sodium hydroxide solution, 1 N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. After removing the drying agent, the solvent was removed under reduced pressure. The residue was crystallized from ethanol. [3R- [3a, 4β (S *)]] - N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) was obtained. a-hydroyyben-

zolacetamide (6.0 g) as white. Solid mp 238-24O ⁰ C. [a _D ] ²⁵ = + 94.6 ° (C = I, MeOH).

¹ H NMR (CDCl ₃ ) S 7.4 (m, 5H), 7.26 (t, J = 1.0 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H ), 6.83 (d, J = 9.0 Hz, 1H), 5.16 (s, 1H), 4.98 (t, J = 9.0 Hz, 1H, 3.8 (i.e. , J = 5.0 Hz, 1H), 3.55 (dd, J = 4.0 & 5.0 Hz, 1H), 1.45 (s, 3H), 1.2 (s, 3 H) .

C ₂ 0 ^H 20 ^N 2 ° 4 ^: CHN

Calculated: 68.17 5.72 7.95

Filled: 67.92 5.49 8.05.

The residual material of the mother liquor was purified by flash chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (3: 7). The residue was crystallized from dichloromethane-isopropyl ether. There was obtained [3S- [3a, 4β (R *)]] - N - (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) - a-hydroxybenzeneacetamide (6.0 g) as a white solid, mp 100-102 ⁰ C (foam), [ _«D] ²⁵ = -26.1 ° (c = 1, MeOH). ¹ H NMR (DMSO-d ₆ ) S 8.45 (d, J = 8.0 Hz, 1H), 7.5 (m, 4H), 7.3 (m, 2H), 7.0 (S, 1H), 6.88 (d, J = 8.0Hz, 1H), 6.2 (s, 1H), 5.57 (d, J = 5.0Hz, 1H) , 5.0 (s, 1H), 4.76 (t, J = 9.0 Hz, 1H), 3.75 (dd, J = 5.0 & 5.0 Hz, 1H), 1 , 40 (S, 3 H), 1.15 (S, 3 H).

^C 20 ^H 20 ^N 2 ^O 4- ° ^{'26 H} 2 ^{O :} CHN

Calculated: 67.30 5.78 7.84 Found: 67.54 - 5.95 7.44.

B. (3S-trans) -4-amino-3 _/ 4-dihydro-3-hydroxy-2 _/ 2-dimethyl-2H-1-benzopyran-6-carbonitrile

A solution of the title compound A [3S- [3a, 4β (R *)]] - N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4 yl) -α-hydroxybenzeneacetamide (2.8g, 7.9mmol) in dioxane (30ml) was added at room temperature with a solution of sulfuric acid (2.5g) in water (12ml). The reaction mixture was refluxed for 24 hours. Then it became

It was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (200 ml). The organic phase was washed with 1N sodium hydroxide solution (50 ml) followed by water (50 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The title compound B (1.6 g) was obtained as an oil: ¹ H NMR (CDCl ₃ ) 6 7.74 (S, 1 H), 7.42 (dd, J = 2.0 & 6.0 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 3.65 (d, J = 10.0 Hz, 1 H), 3.36 (d, J = 10.0 Hz, 1H), 1.53 (s, 3H), 1.23 (s, 3H).

C. (3S-trans) -N "-cyano-N- (6-oano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - phenylguanidine

A solution of N-cyano-N · phenylthiourea (1.7 g, 9.5 mmol) and the title compound B (1.6 g, 7.3 mmol) in dimethylformamide (7 mL) was added under argon at room temperature with 1 - (3-Dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride, (1.8 g, 9.5 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1N hydrochloric acid and ethyl acetate. The organic phase was separated and the aqueous phase reextracted with ethyl acetate. The combined extracts were washed with water, aqueous sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude product purified by flash chromatography on silica gel, eluting with ethyl acetate / hexanes (7: 3) to give a colorless solid (0.7 g). The solid was triturated with ether. The title compound (0.35 g) was obtained, melting at 214-216 ⁰ C.

[O ₀ ] " ⁵ = -34.8 ° (C = 0.417, MeOH) - 1 H NMR (DMSO-dg) S 9.28 (s, 1H), 7.58 (d, J = 8.0 Hz, 3H), 7.35 (m, 4H), 7.15 (m, 1H), 6.90 (d, J = 8.2 HZ, 1H), 5.92 (br S, 1 H), 4.92 (t, J = 9.0 Hz, 1 H), 3.72 (br d, J = 5.9 Hz, 1 U), 1.41, 1.18 (S, 3 H each); ¹³ C NMR (DMSO-dg) 159.2, 156.3, 137.5, 132.5, 132.5, 129.0, 124.8, 124.7, 123.6, 119, 0, 117.8,

117.0, 102.6, 80.4, 70.9, 51.9, · 26.6, 18.6; IR (KBr) 2226, 2179, 1609, 1582, 1491, 1267 cm ^-1 .

^C 20 ^H 19 ^N 5 ° 2 · 0 37H ₂ O: C 19 H 19 N calc .: 65.26 5.40 18 , 02 gef. : 65.62 5.36 , 57 example

(3R-trans-N ^H-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-4-yl) -N · -phenylguanidin

A. (3R-trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile

A solution of [3R- [3a, 4β (S *)]] - N - (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -a-hydroxybenzeneacetamide, Compound 18, Section A, (2.8g, 7.9mmol) in dioxane (30ml) was treated at room temperature with concentrated sulfuric acid (2.5g) and water (12ml). The reaction mixture was refluxed for 24 hours. It was then evaporated under reduced pressure and the residue combined with another batch of the same material and dissolved in ethyl acetate (400 ml). The resulting solution was washed with X η sodium hydroxide solution (50 ml) followed by water (50 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The title compound A (3.7 g) was obtained as an oil. ¹ H NMR (CDCl ₃ ) δ 7.74 (s, 1H), 7.42 (dd, J = 2.0 & 6.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1 H), 3.65 (d, J = 10.0 Hz, 1 H), 3.36 (d, J = 10.0 Hz, 1 H), 1.53 (S, 3 H), 1.23 (s, 3H).

B. (3R-trana) -N ^ -cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - phenylguanidine

A solution of N-cyano-N'-phenyl thiourea (3.9 g, 21.9 mmol) and the title compound A (3.68 g, 16.9 mmol) in dime.

Thy-formamide (20 ml) was added at room temperature under argon with 1- (3-dimethylaminonopropyl) -2-ethylcarbodiimide hydrochloride (4.2 g, 21.9 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1N hydrochloric acid and Esco-gsäureethylester. The organic phase was separated and the aqueous phase reextracted with ethyl acetate. The combined extracts were washed with water, aqueous sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude product triturated with ethyl acetate-ether. A colorless solid (3.5 g) was obtained. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes (7: 3). The solid obtained after evaporation of the solvent was triturated with ether. The title compound (1.8 g) was obtained as a colorless solid, melting at 215-217 ⁰ C.

[a _D] ²⁵ = + 34.8 ° (c = "0.417, MeOH) - ¹ H NMR _(CDCl3 / _DMSO-d6) S 8.8 (s, 1 H), 7.6 (S, 1 H), 7.44 (d, J = 8.0Hz, 1H), 7.35 (d, J = 5.0HZ, 4H), 7.22 (m, 1H), 6.85 (d, J = 8.8Hz, 1H), 6.7 (brs, 1H), 5.0 (t, J = 9.0Hz, 1H), 3.72 (br d, J = 5.3 Hz, IH), 1.48, 1.18 (s, 3 H each); ¹³ C isHR (CDCl ₃ / DMSO-d _{6 /} -59.6, 156.5, 136.6, 132.5, 129.2, 125.7, 124.1, 123.7, 118.9, 118 , 1, 117.2, 103.4, 80.3, 72.8, 52.4, 26.4, 18.6, IR (KBr) 2226, 2179, 1609, 1582, 1491, 1267

cm " ¹ 19 ^N 5 ° 2 •O, 45H ₂ O: 65 C 5 H 18 N ^C 20 ^H calc .: 65 , 01 5 , 42 18 95 Found .: , 18 , 47 , 51st

Example 2 < represents an alternative procedure for Example 18, with the method of this Example 20 being preferred. Further, the 3S, 4R enantiomer of Example 20 represents the preferred compound of the invention.

Example 20

(3S-trans) -N ^u-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-di methyl-2H-l-benzopyran-4-yl) -N ¹ -phenylguanidin

A. [3S- [3a, 4β (S *)]] - N- (6-cyano-3 _/ 4-dihydro-3-hydroxy-2,2-di-methyl-2H-1-iienzopyran-4-yl) -a-hydroxybenzeneacetamide

and

, 4SS (R *)]] - N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-4-yl] -a-hydroxybenzeneacetamide

A solution of (trans) M-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chera., Vol. 26 (1983), page 1582 and J. Med. Chem. 29 (1986), page 2194) (1.64 g, 7.5 mmol), R (-) - mandelic acid (1.14 g ^, 7.5 mmol) and hydroxybenzotriazole hydrate (1.0 g, 7.5 mmol) in dimethylformamide (15 ml) was added at room temperature with dicyclohexylcarbodiimide (1.55 g, 7.5 mmol). The reaction mixture was stirred at room temperature for 20 hours and then cooled in an ice bath. The solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in 5% methanol in chloroform and washed with 1 N sodium hydroxide, 1 N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. After removing the drying agent, the solvent was removed under reduced pressure. The residue was crystallized from ethanol. [3S- [3a, 4β (S *)]] - N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) was obtained. ahydroxybenzene acetamide (0.85 g) as a white solid, mp 235-237 ° C. [a _D ] ²⁵ = -94.9 ° (c = 1, MeOH). ¹ H NMR (DMSO-dg) S 8.45 (d, J = 8.0 Hz, 1H), 7.5 (m, 4H), 7.3 (m, 2H), 7.0 ( S, 1H), 6.88 (d, J = 8.0Hz, 1H), 6.2 (s, 1H), 5.57 (d, J = 5.0HZ, 1H), 5.0 (s, 1H), 4.76 (t, J = 9.0 Hz, 1H),

3.75 (dd, J = 5.0 & 5.0 Hz, 1H), 1.40 (s, 3H), 1.15 (s, 3H).

^C 20 ^H 20 ^N 2 ° 4 ^: CHN

Calculated: 68.17 5.72 7.95

Filled: 68.00 5.52 7.95.

The residual material recovered from the mother liquor was crystallized by flash chromatography on silica gel eluting with hexane-ethyl acetate (3: 7). The product was purified from dichloromethane-isopropyl ether. [3R- [3a, 4β (R *)]] - N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) was obtained. a-hydroxybebenzolacetamid as a white solid, mp 100-102 ⁰ C (foaming). [a _D ] ²⁵ = + 25.6 ° (C = 1, MeOH). ¹ H NMR _(CDCl3) S 7.4 (m, 5 H), 7.26 (t, J = 1.0 Hz, 1 H), 6.97 (d, J = 9.0 Hz, 1 H ), 6.83 (d, J = 9.0 Hz, 1H), 5.16 (s, 1H), 4.98 (t, J = 9.0 Hz, 1H), 3.8 ( d, J = 5.0 Hz, 1 H), 3.55 (dd, J = 4.0 & 5.0 Hz, 1 H), 1.45 (S, 3 H), 1.2 (s, 3H)

C ₂₀ H ₂₀ N ₂ O ₄ -0.25 H ₂ O: CHN

Calculated: 67.30 5.78 7.84 Found: 67.17 5.87 7.44

B. (3S-trans) -4-amino-3,4-dihydro-3-hydroxy-2,2 - <; imethyl-2H-1-benzopyran-6-carbonitrile

A solution of [3S- [3a, 4β (S *)]] - N - (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -a-hydroxybenzeneacetamide, title compound A, (6.09g, 17.0mmol) in dioxane (60ml) at room temperature was added a solution of sulfuric acid (6.0g) in water (30ml). The reaction mixture was refluxed for 24 hours. It was then evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The organisate phase was washed with 1N sodium hydroxide solution and then with water and dried over anhydrous magnesium sulfate. The solvent was evaporated. The title compound B was obtained as an oil:

¹ H NMR (CDCl ₃ ) S 7.74 (s, 1 H), '7.42 (dd, J = 2.0 & 6.0 Hz, 1 H), 6.82 (d, J = 8, 0Hz, 1H), 3.65 (d, J = 10.0Hz, 1H), 3.36 (d, J = 10.0Hz, 1H), 1.53 (s, 3H) , 1.23 (s, 3H).

dimethyl-2H-1-benzopyran-4-yl) -N ¹ -phenylguanidine

A solution of N-cyano-N'-phenylthiourea (2, 11 g, 11.9 mmol) and (3S-trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H 1-l-benzopyran-6-carbonitrile (2.0 g, 9.1 mmol), title compound B, in dimethylformamide (20 ml) was treated at room temperature under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (2 , 23 g, 11.9 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1 N hydrochloric acid and ethyl acetate. The organic phase was separated and the aqueous phase reextracted with ethyl acetate. The combined organic extracts were washed with water, sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes (7: 3). A colorless solid was obtained which was triturated with ether. The title compound (0.35 g) was obtained, melting at 215-216 ⁰ C.

[a] _D ²⁵ = -33.5 ° (C = 1, MeOH). ¹ H NMR (DMSO-dg) <S 9.28 (s, 1H), 7.58 (d, J = 8.0Hz, 3H), 7.35 (m, 4H), 7.15 (m, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.92 (br s, 1H), 4.92 (t, J = 9.0 HZ, 1H ), 3.72 (br d, J = 5.9Hz, 1H), 1.41, 1.18 (s, 3H each); ¹³ C NMR (DMSO-dg) 159.2, 156.3, 137.5, 132.6,

132.5, 129.0, 124.8, 124.7, 123.6, 119.0, 117.8, 117.0,

102.6, 80.4, 70.9, 51.9, 26.6, 18.6; IR (KBr) 2226, 2179, 1609, 1582, 1491, 1267 can " ¹ .

C ₂₀ H ₁₉ N ₅ O ₂ • 0 , 24H ₂ O: 65 C 5 H 19 N calc .: 65 , 26 5 40 18 , 02 Found .: , 62 , 36 , 57

59 OV? 75

HPLC: 99.5%, Chiracel OD column / hexanes (80%), isopropanol (20%), formic acid (0.1%).

Example 21

(Trans) -4F [2- (cyanoimino) tetrahydro-l (2H) -pyrimidinyl] -3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-6-earbonitril

A. (trans) -4- [(3-aminopropyl) amino] -3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile

A suspension of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (prepared according to Evans et al., J. Med. Cheir., Vol. 26 (1983) , Page 1582 and J. Med. Ex., Vol. 29 (1986), page 2194) (1.0 g, 5.0 mmol) in ethanol (5.0 mL / j was incubated with 1.3-diaminopropane (2 The reaction mixture was stirred at room temperature for 36 hours, the solvent was removed under reduced pressure, and the residue was dried using a vacuum pump for 5 hours to give the title compound A (1.3 g) as colorless foam This material was used without purification for the next step.

B. (trans) -4- [2- (oyanoimino) -tetrahydro-l (2H) -pyrimidinyl] -3,4-dihydro-3-hydroxy-2, Σ-αΙιηβίΙγγ- ^ Η-ΐ-οβηζοργΓβη-β- οβΓ-bonitril

A solution of the title compound A (1.3 g, 4.7 mmol) in ethanol (5 mL) was added at room temperature with triethylamine (1.3 mL, 9.4 mmol) followed by dimethyl N -cyanodithioimnocarbonate (1 , 5 g, 9.4 mmol of 90%), stirring at room temperature. The reaction mixture was heated to 80 ^° C. for 3 hours and then cooled to ambient temperature. After evaporation of the solvent gave a pale yellow foam (1.5 σ). This material was taken up in methanol (20 ml). The resulting suspension was treated with mercuric acetate (2.0 g, 6.1 mmol). The

60 zs ^ f 15

The reaction mixture was stirred for 2 hours at room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and basified with 2.5 N sodium hydroxide solution to the pH of about 9.0. The product was extracted with 10% methanolic chloroform (3x). The combined extract was washed with brine to give a thick emulsion. The biphasic mixture was filtered through a celite pad. The organic phase was separated and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography (5% methanol in chloroform) on silica gel. This gave a colorless residue (0.5 g) which was purified from isopropyl ether-ethyl acetate. The title compound was obtained as a white powder, melting at 152-153 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 7.60 (., J = 7.0 Hz, 1H), 7.40 (s, 1H), 7.0 (d, J = 9.0, 1 H), 5.85 (d, J = 5.2 Hz, 1 H), 5.6 (d, J = 10.5 Hz, 1 H), 3.8 (dd, J = 5.0 Hz, 1H), 3.2 (m, 4H), 2.9 fbr d, IH), 1.54, 1.26 (s, 3H each); ¹³ C NMR (DMSO-d ₆ ) 164.5, 156.8, 133.2, 131.6, 118.9, 118.2, 118.0, 103.1, 80.4, 67.3, 51 , 2, 40.3, 26.6, 18.6; IR (KBr) 1268.7, 1316.8, 1402.2, 1489.5, 1558.1, 1580.4, 2174.7, 3421.3 cm ^-1 . C ₁₇ H ₁₉ N ₅ O ₂ -0, 42H ₂ O: CHN

Calc .: 61.33 6.01 21.04 Found: 61.31 6.02 21.06.

Example 22

(trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - (4-pyridinylmethyl ) guanidine

A suspension of (trans) -4 - [[(cyanoimino) phenoxymethyl] amino] -3,4-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.0 g, 2, 76 mmol), compound of example 7, section A, in isopropanol (5 ml) was treated at room temperature with 4- (aminomethyl) -pyridine (1.0 ml). The reaction mixture was stirred for 4 hours at room temperature and

61 Wt Ϊ15

then heated under reflux for 16 hours. Subsequently, the reaction mixture was cooled to ambient temperature and the precipitated solid was filtered off. The product was recrystallized from ethyl acetate. The title compound (0.76 g) was obtained as a colorless solid, melting at 156-158 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 8.53 (d, J = 6.0 Hz, 2H), 7.9 (m, 1H), 7.59 (dd, J = 3.0 & 6 , 0 Hz, 1 H), 7.44 (s, 2 H), 7.31 (d, J = 6.0 Hz, 2 H), 6.91 (d, J = 9.0 Hz, 1 H ), 5.9 (s, 1H), 4.87 (m, 1H), 4.48 (t, J = 2.0 & 6.0 Hz, 2H), 3.7 (m, 1 H), 1.99 (s, 3H), 1.18 (s, 3H); ¹³ C NMR (DMSO-d ₆ ) 160.4, 156.2, 149.4, 132.6, 132.3, 124.7, 121.7, 117.8, 117.4, 102.6, 80 , 4, 71.0, 51.5, 43.4, 26.5, 18.6; IR (KBr) 1125.2, 1490.2, 1524.1, 1577.8, 1611.3, 2170.4, 2224.9, 3429.7 cm ^-1 · ^C 20 ^H 20 ^N 6 ^O 2- ° ' ^2H 2 ^0: CHN

Calc .: 63,22 5,41 22,12

F .: 63.42 5.17 21.92. Example 23

(trans) W-Cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - (3-pyridinylmethyl) guanidine

A suspension of (trans) -4 - [[(cyanoimino) phenoxymethyl] amino] -3,4-dihydroxy-2,2-di-ethyl-2H-1-benzopyran-6-carbonitrile (1.0 g, 2, 76 mmol), compound of example. 7, section A, in isopropanol (5 ml) was treated at room temperature with 3- (aminomethyl) -pyridine (1.0 ml). The reaction mixture was stirred for 4 hours at room temperature and then heated under reflux for 16 hours. The reaction mixture was then concentrated under reduced pressure and the resulting solid crystallized from ethyl acetate. The title compound (0.72 g) was obtained as a colorless solid, melting at 226-228 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 8.55 (s, 1H), 8.49 (d, J »2.0Hz, 2H), 7.85 (m, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 HZ, 1H), 7.40 (m, 3H), 6.91 (d, J = 8 , 0 Hz, 1 H), 5.85 (s,

1H), 4.82 (m, 1H), 4.48 (m, 2H), 3.74 (m, 1H), 1.40 (s, 3H), 1.17 (s, 3 H); ¹³ C NMR 160.43, 156.2, 148.6, 148.2, 134.6, 134.2, 132.7, 132.2, 124.8, 123.4, 118.9, 117.9 , 117.5, 102.6, 80.4, 71.0, 51.5, 42.1, 26.6, 18.7 / IR (KBr) 1125.2, 1490.1, 1524.1, 1577 , 8, 1611.3, 2170.4 2224.9,

3429 , 7 cm ". 1 7H ₂ O: C H 41 22 N ^C 20 ^H 20 N ₆ O ₂ -O, calc .: 63.22 5, 32 22 12 Found .: 63.08 5, , 38th , example 24

(trans) -N ^M -Cyano-N- (6-ethynyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ -phenylguanidine

A. I - ((1,1-dimethyl-2-propynyl) oxy) -4-iodobenzene

A solution of 3-chloro-3-methyl-l-butyne (10.0g, 97.9mmol), 4-iodophenol (15.0g, 68.4mmol), sodium hydroxide (3.90g, 97, 5 mmoles) and tetrabutylammonium hydrogensulfate (9.33 g, 27.5 mmoles) in methylene chloride (50 ml) and water (50 ml) was stirred at room temperature for 19 days. After separating the two phases, the organic phase was washed with 1N sodium hydroxide solution and then with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1N hydrochloric acid, 1N sodium hydroxide solution, water and brine, and dried over anhydrous magnesium sulfate. After removal of the drying agent, the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with toluene / hexane (1:10). The title compound was obtained as an oil (5.78 g, 20.2 mmol) in 30% yield. ¹ H NMR (CDCl ₃ ) S 7.56 (d, J = 8.7 Hz, 2 H), 6.98 (d, J = 8.8 HZ, 2H), 2.56 (s, IH), 1.63 (s, 6H); ¹³ C NMR (CDCl ₃ ) S 155.4, 137.8, 123.5, 86.0, 85.6, 74.3, 72.6, 29.5.

B. 2,2-dimethyl-6-iodo-2H-1-benzopyran

The title compound A (3.91 g, 13.7 mmol) was heated to 17O ⁰ C in an oil bath for 2 hours. After cooling, the crude product was purified by flash chromatography on silica gel eluting with toluene / hexane (1:20). The title compound was obtained as an oil (3.26 g, 11.4 mmol) in 83% yield. ¹ H NMR (COCl ₃ ) S 7.34 (dd, J ₁ = 1.8, J ₂ = 2.4 Hz, IH), 7.24 (d, J = 0.9 Hz, IH), 6, 52 (d, J = 8.8 Hz, IH), 6.21 (d, J = 10.0 Hz, IH), 5.58 (d, J = 10.0 Hz, IH), 1.40 ( S, 6H); ¹³ C NMR (CDCl ₃ ) δ 152.8, 137.5, 134.7, 131.6, 123.6, 121.1, 118.6, 82.4, 76.4, 27.9.

C. 2,2-dimethyl-6- (trimethyl-ialyl) -ethynyl) -2H-1-bonzopyran

A solution of the title compound B (1.32 g, 4.61 mmol), of trimethyl- ((trimethylstannyl) -ethynyl) -silane (1.60 g, 5.69 mmol), lithium chloride (0.62 g (14), 6 mmol) and tetrakis (triphenylphosphine) palladium (0.69 g, 0.60 mol) in dioxane (16.5 ml) was stirred for 5 hours in an oil bath at 65 ⁰ C under argon. Then, the Reaktionsgeraisch to room temperature The resulting residue was combined with the material similarly prepared on a 2.42 mmol scale, the combined material was rinsed with toluene / hexane (1:10), and the filtrate was evaporated under reduced pressure. the crude product was purified by flash chromatography on silica gel eluting with toluene / hexane (1:10). this gave the title compound C as an oil (1.82 g, 7.00 mmol) in a yield of 100%. ¹ H NMR (CDCl ₃ ) S 6.98 (dd, J ₁ = 2.3, J ₂ = 8.2 Hz, IH), 6.87 (d, J = 1.8 Hz, IH), 6.44 ( d, J - 8.2 HZ, IH), 6.02 (d, J = 9.4 Hz, IH), 5 , 38 (d, J = 10.0 Hz, IH), 1.20 (S, 6H), 0.00 (s, 9H); ¹³ C NMR (CDCl ₃ ) δ 153.4, 133.0, 131.2, 130.0, 121.6, 121.0, 116.3, 115.2, 105.2, 92.1, 76, 7, 28,1, 0,1.

C ₁₆ H ₂₀ OSi: 74 C 7 H calc .: 75 , 94 7 , 86 gef. : 19 , 61

D. (ice) -la, 7b-dihydro-2,2-dimethyl-6 - ((trimethylsilyl) ethynyl) -2H-oxireno (c) - (1) -benzopyran

A solution of the title C compound (1.37 g, 5.34 mmol) and sodium bicarbonate (2.33 g, 27.7 mmol) in methylene chloride (27 ml) and water (27 ml) at 0 ⁰ C and the 3- Chlorperoxybenzoic acid (1.51 g with a purity of 80-85%, 7.01 mmol), after a stirring time of a few minutes, the ice bath was removed and the reaction mixture was stirred for 9 hours at room temperature. After adding methylene chloride to the reaction mixture, the organic phase was separated and washed with water and then with brine, dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with hexane / ethyl acetate (10: 1). Recovered starting material (0.47 g) and the title compound as an oil (0.53 g, 1.95 mmol) were obtained in 36% yield. ¹ H NMR (CDCl ₃ ) δ 7.24 (d, J = 1.8 Hz, 1 H), 7.11 (dd, J ₁ = 1.78, J ₂ = 2.3 Hz, IH), 6 , 49 (d, J = 8.2 Hz, IH), 3.62 (d, J = 4.1 HZ, IH), 3.25 (d, J = 4.1 Hz, IH), 1.34 (s, 3H), 1.00 (s, 3H), 0.00 (S, 9H); ¹³ C NMR (CDCl ₃ ) S 152.9, 134.1, 133.4, 120.0, 118.1, 103.6, 92.9, 73.6, 62.5, 50.5, 25, 6, 22.7, 0.00.

E. (trans) - ^ amino-e-ethynyl-a ^ -dihydro ^ H-l-benzopyran-aol

A solution of the title compound D (0.53 g, 1.95 mmol) in ethanol (15 mL) and concentrated aqueous ammonium hydroxide (30 mL) was stirred at room temperature for 4 days. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel

Elution with Haxan / ethyl acetate / methanol (5: 5: 1). A partially purified product was obtained. This material was triturated with diethyl ether. The title compound was obtained as a white solid (0.42 g, 1.93 mmol) in a yield of 99%, melting at 132-134 ⁰ C.

¹ H NMR (CDCl ₃ ) S 7.62 (s, IH), 7.38 (dd, J ₁ = 1.2, J ₂ = 1.8 Hz, IH), 6.82 (d, J = 8 , 2, Hz, IH), 3.73 (d, J = 10.0 Hz, IH), 3.45 (d, J = 9.4 Hz, 1 H), 3.10 (s, IH), 2.56 (br s, 3H), 1.59 (S, 3H), 1.30 (s, 3H); ¹³ C NMR (CDCl ₃ ) S 153.0, 132.6, 131.0, 125.7, 117.2, 114.0, 83.6, 78.6, 75.9 75.8,

51 1 , 26.9, 18 ^. 71, C 6 H 6 N ^C 13 H ₁₅ NO ₂ -0, 06 H ₂ O: 71, 52 6 , 98 6 , 42 calc .: 47 / 95 , 47th Found .:

F. (trans) -N "-cyano-N- (6-ethynyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ -phenylguanidine

A solution of the title compound E (0.150 g, 0.69 mmol) and N-cyano-N'-phenylthiourea (0.180 g, 1.0 mmol) in dimethylformamide (5 mL) was treated at room temperature with 1- (3-dimethylaminopropyl). 2-ethylcarbodiimide hydrochloride (0.200 g, 1.0 mmol). The reaction mixture was stirred overnight at room temperature and then the solvent was removed under reduced pressure. The residue was shaken out with water and ethyl acetate. The organic phase was separated and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with hexane / ethyl acetate / ethanol (30: 10: 5). A partially pure product was obtained. This material was triturated with diethyl ether. The title compound (0.12 g, 0.34 mmol) was obtained in a yield of 49%, melting at 220-222 ⁰ C (dec.). ¹ H NMR (CDCl ₃ ) δ 7.20-7.40 (m, 7H), 6.70 (d, J = 8.2 Hz, IH), 5.00 (d, J = »10.0 Hz , IH), 3.67 (d, J = 9.4 Hz, IH), 3.34 (s, IH), 1.44 (s, 3H), 1.24 (s, 3H); ¹³ C NMR (CDCl ₃ ) S 161.6, 154.6,

66 Z3 <t '/ 75

138.2, 133.7, 132.8, 130.5, 127.2, 125.7, 123.9, 118.9,

118.3, 116.0, 84.3, 80.5, 77.2, 74.6, 54.0, 27.1, 18.6

C ₂₁ H ₂₀ N ₄ O ₂ -0.32 H ₂ O: CHN

Calculated: 68.89 5.68 15.31 found: over 9.11 5.55 15.09.

Example 25

(trans) -N ^H-cyano-N- (3,4-dihydro-6- (phenylethynyl) -2H-l-benzopyran-4-yl) -N ¹ -phenyl .guanidin!

A. 2,2-Dimethyl-6- (phenylethynyl) -2H-1-benzopyran

A solution of the title compound B of Example 24 (1.69 g, 5.91 mmol) and phenylacetylene (2.0 mL, 18.1 mmol) in diethylamine (30 mL) was added at room temperature under an argon atmosphere with bis ( triphenylphosphine) -palladiuron (II) chloride (0.40 g, 0.572 mmol) and copper (I) iodide (0.22 g, 1.41 mmol). After stirring for 1 h at room temperature, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the insoluble material was filtered off. The filtrate was evaporated under reduced pressure. The residue was redissolved in toluene / Hoxan (1:10) and the insoluble material was filtered off. The filtrate was evaporated under reduced pressure and the crude product was purified by flash chromatography on silica gel eluting with toluene / hexane (1:10). The title compound was obtained as an oil (1.43 g, 5.49 mmol) in 92% yield. ¹ H NMR (CDCl ₃ ) 6 7.47-7.50 (m, 2H), 7.24-7.31 (m, 4H), 7.14 (d, J = 2.4 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 6.26 (d, J = 10.0 Hz, IH), 5.58 (d, J = 9.4 HZ, IH), 1, 40 (s, 6H); ¹³ C NMR (CDCl ₃ ) δ 153.2, 132.5, 131.3, 131.2, 129.5, 128.2, 127.8, 123.6, 121.6, 121.1, 116, 4, 115.2, 89.4, 87.8, 76.7, 28.0.

For example, 2,2-dimethyl-6- (phenylethynyl) -2H-oxireno- (c) - (1) -benzopyran

A solution of the title compound A (1.14g, 4.38mmol) and sodium bicarbonate (1.86g, 22.1mmol) in methylene chloride (15ml) and water (15ml) was added at ⁰ ° C with 3- Chloroperoxybenzoic acid (1.21 g with a purity of 80-85%, 5.62 mmol) was added. After 5 minutes, the ice bath was removed and the reaction stirred at room temperature for 8 hours. It was then diluted with methylene chloride and the organic phase was recovered. This phase was then washed with water and then with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The material was purified by flash chromatography on silica gel eluting with hexane / ethyl acetate (10: 1). Recovered starting material (0.17 g) was obtained and the title compound as an oil (0.74 g, 2.68 mmol) in 61% yield. ¹ H NMR (CDCl ₃₎ "y from 7.42 to 7.64 (m, 7H), 6.90 (d, J = 8.8 Hz, IH), 3.99 (d, J« 4.7 HZ , IH), 3.60 (d, J = 4.7 Hz, IH), 1.69 (s, 3H), 1.38 (s, 3H); ¹³ C NMR (CDCl 3) S 152.8, 133.7, 132.9, 131.4, 128.3, 128.0, 123.4, 120.2, 118.2, 115.9, 88.9 , 88.3, 73.6, 62.5, 50.6, 48.2, 22.7.

C (trans) - <- amino-3 _f 4-dihydro-2,2-dimethyl-6-phonylethinyl) -2H-l-benzopyran-3-ol

A solution of the title compound B (0.71 g, 2.55 mmol) in absolute ethanol (20 ml) and concentrated aqueous ammonium hydroxide (40 ml) was stirred for 7 days. Then the solvents were removed under reduced pressure. The crude product was triturated with hexane and diisopropyl ether. The title compound was obtained as a white solid (0.64 g, 2.18 mmol) in a yield of 86%, melting at 162-164 ⁰ C.

¹ H NMR (CDCl ₃ ) S 7.36-7.67 (m, 7H), 6.86 (d, u ^r = 8.2 Hz, IH), 3.78 (d, J = 10.0 Hz , IH), 3.48 (d, J = 10.0 Hz, IH), 2.51 (br S, 3H), 1.62 (s, 3H), 1.32 (S, 3H); ¹³ C NMR (CDCl3)

S 152.7, 132.1, 131.4, 130.4, 128.3, 128.0, 125.6, 122.8, 117.3, 115.0, 88.6, 87.1, 78 , 5, 76.0, 51.2, 26.9, 18.7

C ₁₉ H ₁₉ O ₂ NO, 28 H ₂ O: CHN

Calc .: 76.46 6.61 4.69

F .: 76.39 6.52 4.76.

D. (trans) -W-cyano-N- (3,4-dihydro-6- (phenylethynyl) -2H-1-benzopyran-4-yl) -N ¹ -phenyl-guanidine

A solution of the title C compound (O ₁ .64 g, 2.18 mmol) and N-cyano-N'-phenylthiourea (0.56 g, 3.16 mmol) in dimethylformamide (16 ml) was treated at room temperature with l- (3-Dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (0.60 g, 3.49 mmol). The reaction mixture was stirred for 2 days at room temperature and then the solvent was removed under reduced pressure. The residue was shaken out with ethyl acetate and water. The organic phase was collected and washed with water and then with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with hexane / ethyl acetate / ethanol (10: 10: 1). The resulting partially purified material was triturated with diisopropyl ether. The title compound was obtained as a white solid (0.46 g, 1.05 mmol) in a yield of 48%, mp 175-177 ⁰ C. ¹ H NMR (DMSO-dg) «S 9.42 (s, IH ), 7.82 (d, J = 8.8 Hz, IH), 7.20-7.75 (m, 14H), 6.88 (d, J = 9.4 HZ, IH), 5.59 (br S, IH), 5.02 (dd, J ₁ = 8.8, J ₂ = 9.4 Hz, IH), 3.80 (br d, J = 9.4 HZ, IH), 1, 50 (s, 3H), 1.27 (s, 3H); ¹³ C NMR (DMSO-dg) S 159.5, 153.2, 138.0, 132.2, 131.6,

131.3, 129.3, 129.0, 128.0, 124.9, 124.1, 123.7, 122.9,

117.4, 114.3, 89.7, 88.3, 79.9, 71.6, 52.5, 27.1, 18.8.

u. Z .: Z 904 DD

Note: F-359,236 / HA488-S

E.R. Squibb & Sons, Inc.

⁶⁹ 21H 7 <iS

Example 26

(Trans) HN "-cyano-N- (3,4-dihydro-3-hydroxy-2,2-dimethyl-6-

nitro-2H-1-benzopyran-4-yl) -N ¹ -phenylguanidine

A solution of trans-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyi-6-nitro-2H-1-benzopyran (2.0 g, 8.39 mmol, prepared according to Evans et al , J. Med. Chem. (1983) 26, 1582 and J. Med. Chem. (1986) 29, 2194) and N-cyano-N ¹ -phenylthio

urea (1.93 g, 10.91 mmol) in N, N-dimethylformamide (10 mL) was added with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide.HCl (2.09 g, 10.91 mmol). The reaction mixture was stirred under argon at room temperature for 2 hours and extracted by shaking with ethyl acetate and 5% hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed successively with distilled water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate.

² ^ The solvent was removed under reduced pressure. There were obtained 2.79 g of crude product. This was recrystallized twice from the minimum amount of hot ethanol. Here, 1.01 g of the title compound was obtained as an off-white solid. The combined mother liquors were chromatographed on silica gel, eluting with 1: 1 ethyl acetate / hexane. An additional 0.49 g of the product was obtained.

¹ H NMR (DMSO-d ₆ ) δ 9.39 (broad s, IH), 8.07 (s, IH), 8.03 (d, J = 2.35 Hz, IH), 7.69 (i.e. , J = 8.21 Hz, IH), 7.40-7.34 (m, 4H), 7.18-7.14 (m, IH), 6.96 (d, J = 8.80 Hz, IH), 5.96 (broad s, IH), 4.98 (m, IH), 3.77 (d, J = 9.39 Hz, IH), 1.45 (S, 3H), 1.22 (s, 3H), ¹³ C NMR (DMSO-dg) δ 159.18, 158.1.4, 140.63, 137.44, 129.06, 124.77. 124, 48, 124, 33, 123, 99, 117, 117, 54, 116, 90, 81, 70, 70, 51, 97, 26, 51, 18, 62.

C ₁₉ H ₁₉ N ₅ O ₄ : 59 C H el 18 N calc .: 59 , 83 5.02 18 , 37 Found .: 60 4.93 27 , 29 Beispj

(trans) - !! "- cyano-N- (6-cyano-3, 4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-4-yl) -N ¹ - (4- cyanophenyl) guanidine

A. N -cyano-N'-4-cyanophenylthiourea

The suspension of monosodium cyanamide (4.3 g, 67.2 mmol) in absolute ethanol (170 mL) was slowly added with 4-cyanophenyl isothiocyanate (10.75 g, 67.2 mmol). The reaction mixture was stirred for 1 hour at room temperature and then heated to 75 ^° C. for 4 hours. The reaction mixture was cooled to room temperature and the colorless solid filtered off and washed with ethanol. There were obtained 10.0 g of the title compound A, mp> 250 ° C.

 20

B. (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - (4 -cyanophenyl) guanidine

The solution of the title compound A (1.2 g, 5.96 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.0 g, 4.59 mmol, prepared according to Evans et al., J. Med. Chem. (1983) 26, 1582 and J. Med. Chem. (1986) 29, 2194) in dimethylformamide (5 ml). has been

^OKJ under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.17 g, 5.96 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1N hydrochloric acid and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate was

the solvent was evaporated and the colorless residue crystallized from ethyl acetate. 0.52 g of the title compound were obtained, mp 261-262 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 8.24 (m, 3H), 7.63 (m, 3H), 6.94 (d, J =

8.7 Hz, IH), 6.1 (wide s, IH), 4.92 (t, J = 9.0 Hz, IH), 3.68 (wide d, J = 5.2 Hz, IH) , 1.44, 1.20 (s, 3H each). ¹³ C NMR (DMSO-d ₆ ) <S 158.7, 156.3, 145.1, 142.4, 132.9, 124.9, 124.0, 121.2, 119.1, 117.9 , 116.3, 102.7, 80.4, 70.9, 51.9, 26.6, 18.6. IR (KBr) 3421.9, 2226.0, 2183.6, 1612.6, 1587.5, 1491.1, 1265.4 cm ^-1 .

^C 21 ^H 18 ^N 6 ° 2 •O, 44 H ₂ O: C 28 4 H 21 N calc .: 63.96 4 , 82 20 , 32 Found .: 64.36 65 , 94 example

(trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - (4-methoxyphenyl ) guanidine

A. N -cyano-N ¹ - (4-methoxy) -phenylthiourea

The suspension of monosodium cyanamide (1.95 g, 30.3 mmol) in absolute ethanol (50 mL) was slowly added with 4-methoxyphenylisothiocyanate (5.0 g, 30.3 mmol). The reaction

^The mixture was stirred at room temperature for 1 hour and then heated at 75 ^° C. for 4 hours. The reaction mixture was cooled to room temperature, the colorless solid was filtered off and washed with ethanol. There were obtained 5.4 g of the title compound A, mp> 250 ° C.

B. (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - (4 methoxyphenyl) guanidine

The solution of title compound A (1.23 g, 596 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1 , 0 g, 4.59 mHol prepared according to

JFH

Evans et al., J. Med. Chem., (1983) 26, 1582 and J. Med. Chem. (1986) 29, 2194) in dimethylformamide (5 ml) was treated under argon with 1- (3-dimethylaminopropyl) -. 2-ethylcarbodiimide hydrochloride (1.17 g, 5.96 mmol). The reaction mixture was stirred at room temperature for 2 hours and then extracted by shaking with 1 N hydrochloric acid and ethyl acetate. The aqueous phase was extracted again with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the colorless residue was crystallized from ethyl acetate. There was obtained 0.53 g of the title compound, mp 228-229 ° C

¹ H NMR (DMSO-d ₆ ) <S 9,15 (s, IH), 7,66 (m, 2H), 7,33 (d, J =

9.4 Hz, 3H), 6.99 (t, J = 8.8 & 8.2 Hz, 3H), 5.88 (broad s, IH), 4.97 (t, J = 8.8 & 9.4Hz, IH), 3.83 (s, 3H), 3.38 (m, H), 1.48, 1.25 (s, 3H each). ¹³ C NMR (DMSO-d ₆ ) S 15f, 6, 157.1, 156.2, 132.5, 132.3, 131.6, 129.6, 126.6, 125.0, 117.8, 114.2, 102.5, 80.4, 70.6, 55.2, 51.6, 26.6, 18.5.

IR (KBr) 2978.3, 2179.7, 1579.8, 1491.1, 1244.2 cm ^-1 .

^C 21 ^H 21 ^N 5 ° 3 ^: 64 C H 29 17 N calc .: 64 , 43 5.41 17 90 Found .: 12 5.36 , 82 example

N "-cyano-N- (6-cyano-3,4-dihydro-2, 2-dimethyl-2H-l-benzopy-

ran-4-yl) -N ¹ -phenylguanidine

A. 6-Cyano-3 _/ 4-dihydro-2,2-dimethyl-2H-1-benzopyran

A solution of 6-cyano-2,2-dimethyl-2H-1-benzopyran (5.5 g, 29.7 mmol, prepared according to Evans et al., J. Med. Chem., (1983) 26, 1582 and J. Med. Chem. (1986) 29, 2194) in anhydrous ethanol (40 ml) was treated with palladium-on-carbon (0.35 g) and under hydrogen gas for 2 hours

touched. The catalyst was filtered through Celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain 5.71 g of a yellow oil. The crude product was dissolved in 60 ml of ethyl acetate and washed successively with 5% hydrochloric acid solution (60 ml), saturated sodium bicarbonate solution (60 ml) and saturated sodium chloride solution (60 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 5.14 g of the title A compound as a yellow solid (m.p. 30-31 ⁰ C) was obtained, which was used in the next step without further purification

¹ H NMR _(CDCl3) S 7.37 (s, IH), 7.34 (s, IH), 6.80 (d, J = 8.8 Hz, IH), 2.78 (dd, 2H) , 1.80 (dd, 2H), 1.35 (s, 6H). ¹³ C NMR (CDCl ₃ ) A 157.95, 133.82, 131.34, 122.07, 119.53, 118.24, 102.66, 75.76, 32.13, 26.81, 22, 06

C ₁₂ H ₁₃ NO: CHN

Calculated: 76.98 7.00 7.48

Filled: 77.03 7.02 7.58 20

B. ^ bromo-e-cyano-S, 4-dihydro-2,2-dimethyl-2H-1-benzopyran

To a solution of the title compound A (6.40 g, 34.18 mmol) in carbon tetrachloride (90 mL) was added N-bromosuccinimide (6.69 g, 37.6 mmol, 1.1 eq.). The solution was purified with argon. A solution of azobisisobutyronitrile (0.4 g, 3.42 mmol) in carbon tetrachloride (10 mL) was added. The reaction mixture was heated at reflux for 1/2 hour with simultaneous irradiation with

³ ^ high-intensity visible light. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 75 ml of ethyl acetate. The solution was washed successively with distilled water (4 × 75 ml), saturated sodium hydrogencarbonate solution (75 ml) and saturated sodium chloride solution (75 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 9.51 g of an orange

A waxy solid was obtained, which was triturated with cold pentane to give 7.19 g of a beige solid. This was recrystallized from about 25 ml Essigsäureethylestcr in hexane (10:90), whereby 4.60 g of the title compound B was obtained as off-white needles, mp 94-95 ⁰ C. The mother liquors were combined and chromatographed on silica gel, eluting with hexane / Ethyl acetate (19: 1) was eluted. An additional 2.26 g of de & product was obtained.

¹ H NMR (CDCl ₃ ) δ 7.86 (d, J = 1.17 Hz, IH), 7.42 (dd, J = 1.76 and 8.79 Hz, IH), 6.82 (d, J = 8.80 Hz, IH), 5.35 (dd, IH), 2.45 (m, 2H), 1.51 (s, 3H), 1.31 (s, 3H). ¹³ C NMR (CDCl ₃ ) δ 156.71, 136.25, 133.21, 122.61, 118.87, 103.81, 76.54, 43.57, 40.34, 28.36, 25, 45th

C ₁₂ H ₁₂ NBrO: CHN Br

calculated: 54.16 4.45 5.26 30.02

F .: 54.55 4.62 5.46 29.86

C. 4-Azido-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran

A solution of the title compound B (6.73 g, 25.29 mmol) in anhydrous N, N-dimethylformamide (100 mL) was treated with sodium azide (3.79 g, 50.57 mmol, 2 equiv) and left under argon for 4 h stirred at room temperature. The reaction ² "tion mixture was partitioned between 100 ml ethyl acetate and 200 ml of distilled water. The organic layer was separated and the v / äßrige layer with 100 ml of ethyl acetate. The combined organic layers were washed successively with distilled water, saturated sodium bicarbonate solution and saturated sodium chloride solution The solvent was evaporated under reduced pressure to give 5.62 g of an orange gum which was triturated with pentane to give 4.5 g of the title compound C as an off-white solid, m.p. -64 ⁰ C.

JΊΗ

¹ H NMR (CDCl ₃ ) δ 7.69 (s, IH), 7.46 (d, J = 8.80 Hz, IH), 6.86 (d, J = 8.21 Hz, IH), 4 , 59 (dd, J = 6.45 and 2.34 Hz, IH), 2.24 (m, IH), 2.01 (m, IH), 1.49 (s, 3H), 1.36 ( s, 3H), ¹³ C NMR (CDCl ₃ ) δ 157.66, 133.79, 133.41, 121.20, 119.24,

104,21 _; 76.80, 53.73, 38.30, 28.97, 26.29.

D, 4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran

A solution of the title compound C (2.00 g, 8.77 mmol) in absolute ethanol (50 ml) was treated with 10% palladium on carbon (0.25 g) and stirred under hydrogen gas at room temperature for 1.25 hours , The reaction mixture was filtered to remove the catalyst. The filtrate was acidified to pH 1-2 with concentrated hydrochloric acid (0.85 ml) and concentrated under reduced pressure to a white solid. The crude amine hydrogen chloride was dissolved in 100 ml of distilled water and extracted with ethyl acetate. The organic phase was discarded. The aqueous phase was adjusted to pH 11-12 with 50% sodium hydroxide solution and extracted with ethyl acetate. The extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 1.542 g of the title compound D as a yellow oil, which solidified on standing. The product was used in the next step without further purification.

¹ H NMR (DMSO-d ₆ ) δ 8.01 (s, IH), 7.51 (d, J = 8.21 Hz, IH), 6.82 (d, J = 8.21 Hz, IH) , 3.86 (dd, III), 2.07 (dd, J = 5.87 and 13.49 Hz, IH), 1.56 (m, IH), 1.39 (s, 3H), 1, 24 (s, 3H). ¹³ C NMR (DMSO-d ₆ ) δ 156.82, 132.51, 131.59, 129.40, 119.47, 117.45, 101.70, 76.99, 43.13, 42.47, 29.39, 24.70.

E. N ^M-cyano-N- (6-oyano-3,4-dihydro-2, 2-dimethyl-2H-l-benzopyran-4-yl) -N ¹ -phenyl guanidine!

J9H

A solution of the title compound D (1.3 g, 6.43 mmol), N-cyano-N'-phenyl thiourea (1.48 g, 8.36 mmol) and 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide HCl (1.60 g, 8.36 mmol) in N, N-dimethylformamide (6.5 mL) was allowed to stand for 2 hours. Argon stirred at room temperature. The reaction mixture was shaken out with ethyl acetate and a 5% hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with distilled water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to obtain 1.67 g of an off-white solid. The crude material was chromatographed on silica gel, eluting with hexane / ethyl acetate

(1: 1) was eluted. Similar fractions were combined and evaporated to give 1.24 g of an off-white solid. This was recrystallized from the minimum amount of hot ethanol to obtain 780 mg of the title compound were obtained as a white solid, mp 223-225 ⁰ C.

¹ H NMR (DMSO-d ₆ ) S 9.31 (s, IH), 7.68 (s, IH), 7.56 (m, 2H), 7.34 (m, 4H), 7.18 ( m, IH), 6.89 (d, J = 8.79 H, LH), 5.18 (m, IH), 2.19 (m, IH), 1.90 (m, IH), 1, 40 (s, 3H), 1.30 (s, 3H), ¹³ C NMR (DMSO-d ₆ ) δ 158.26, 157.22, 137.38, 132.51,

132,17, 128,94, 124,94, 124,05, 123,82, 119,09, 118,09, 116,76, 102,10, 77,17, 4 '., 48, 37,57, 29:13, 24:15

C ₂₀ II ₁₉ N ₅ O * 0.2H ₂ O: CHN

calculated: 68.83 5.60 20.07

Filled: 68.96 5.43 19.82 30

Example 30

(trans) -N "-cyan-Ν- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dime-

thyl-2H-1-benzopyran-4-yl) -N ¹ - (4-nitrophenyl) guanidine

A. N-cyano-N-4-nitrophenylthiourea

The suspension of monosodium cyanamide (6.4 g, 100 mmol) in absolute ethanol (170 mL) was slowly added with (4-nitrophenyl) isothiocyanate (12.5 mL, 104.5 mmol). The reaction mixture was stirred for 1 hour at room temperature and then heated to 75 ^° C. for 4 hours. The reaction mixture was cooled to room temperature, the colorless solid filtered off and washed with ethanol to give the title compound A, 13.6g, mp> 250 ° C.

B. (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N · - (4 -nitrophenyl) guanidine

The solution of the title compound A (1.3 g, 5.96 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.0 g, 4.59 mmol, prepared according to Evans et al., J. Med. Chem. (1983) 26, 1582 and J. Med. Chem. (1986) 29, 2194) in dimethylformamide (5 ml). was treated under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.17 g, 5.96 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1 N hydrochloric acid and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with hexane / ethyl acetate (3: 7) followed by chloroform / methanol (8: 2) to give 0.6 g of the product were. The obtained product was triturated with ethyl acetate to give the title compound as a colorless solid mp 250-251 ⁰ C (foaming). ¹ H NMR (DMSO-d ₆ ) δ 8.23 (d, J = 8.8 Hz, IH), 7.88 (d, J =

8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 7.6 Hz, = 2H), 7.01 (d, J = 8 , 8 Hz, IH), 6.10 (broad s, IH), 5.01 (t, J = 8.7 & 9.4 Hz, IH), 3.79 (m, IH), 1.51, 1.28 (s, each

YfH 7 * 5

wells 3H). ¹³ C NMR (DMSO-dg) , S 158.8, 156.3, 142.9, 133.3, 132.9, 124.2, 122.1, 119.1, 117.9, 105.5, 102.7, 80.4, 70.9, 51.9, 26.6, 18.6. IR (KBr) 3387.2, 2986.0, 2224.1, 2185.5, 1612.6, 1568.2, 1520.0, 1342.5, 1265.4 cm " ¹ '

^C 20 ^H 18 ^N 6 ° 4- ° ' ^75H 2 ^O: CHN

calculated: 57.21 4.68 20.02

found: 57.35 4.36 19.71

Example 31 10

(trans) -N- (4-chlorophenyl) -N ⁿ -cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) guanidine

A. N-Cyano-N ¹ - (4-chlorophenyl) thiourea

The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (50 mL) was slowly added with 4-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction mixture was stirred for 1 hour at room temperature and then heated to 75 ^° C. for 4 hours. The reaction mixture was cooled to room temperature, the colorless solid filtered off and washed with ethanol to give 5.4 g of the title compound, mp> 250 ° C.

B. (trans) -N- (4-chlorophenyl) -N'-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4 yl) guanidine

The solution of the title compound A (1.26 g, 5.96 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.0 g, 4.59 mmol, prepared according to Evans et al., J. Med. Chem. (1983) 26, 1582 and J. Med. Chem. (1986) 29, 2194) in dimethylformamide (5 ml). was treated under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.17 g, 5.96 mmol). The reaction mixture was stirred at room temperature for 2 hours and then extracted with 1N hydrochloric acid and ethyl acetate.

telt. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography eluting with a mixture of ethyl acetate / hexane (7: 3). The solid was triturated with ethyl acetate to give 0.7 g of the title compound, mp 216-218 ° C.

¹ H NMR (DMSO-d ₆ ) S 9.43 (s, IH), 7.68 (m, 3H), 7.45 (m, 4H), 6.95 (d, J = 8.8 Hz, IH), 5.99 (broad s, IH), 4.98 (t, J = 9.4 & 8.8 Hz, IH), 3.79 (m, IH), 1.50, 1.27 ( s, 3H each). ¹³ C NMR (DMSO-d ₆ ) δ 159.1, 156.2, 136.5, 132.6, 132.5, 128.8, 125.5, 124.6, 119.0, 117.8, 116.8, 102.6, 804 709 519 265 185 IR (KBr) 3400.7, 2226.0,

80.4 , 6 70.9, 51 , 9, 26 5, 18 ,! 5. IR (KBr) 2181 18 , 1606, 8th, 1575 , 9, 1491.1, 1,267.3 cm " ¹ . ^C 20 ^H ClN ₅ O ₂ : C H N Cl calc .: 60 68 4.58 17, 70 8.96 Found .: 60 40 4.70 17.55 8.68 Example 32

(trans) -N'-cyano-N- (6-cyano-3 _/ 4-dihydro-3-hydr) xy-2 _/ 2-dime

ethyl-2H-1-benzopyran-4-yl) -N ¹ - (2-pyridinylmethyl) -guanidine

A suspension of the title compound A of Example 7 (1.0 g, 2.76 mmol) in isopropanol (5 mL) was treated at room temperature with 2- (aminomethyl) pyridine (1.0 mL). The Reakticvisgemisch was stirred for 4 hours at room temperature and ³ ^ as:... · "Utiter reflux heated for 16 hours, it was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate (2 liters) followed by 10% methanol in chloroform (1 liter) to give 0.8 g of a colorless residue. This was triturated with isopropyl ether to give 0.45 g of the title compound were obtained as a white solid, mp 202-203 ⁰ C.

¹ H NMR (DMSO) <S 8.59 (d, J = 7.4 Hz, IH), 7.79 (m, IH), 7.60 (m, 2H), 7.36 (m, 2H) , 6.91 (d, J = 8.8 Hz, IH), 5.86 (s, IH), 4.87 (broad s, IH), 4.48 (m, 2H), 3.73 (broad s, IH), 1.40 (S, 3H), 1.18 (s, 3H). ¹³ C NMR δ 160.8, 156.2, 148.8, 136.8, 132.8, 132.7, 124.8, 122.3, 121.2, 119.2, 117.8, 102, 6, 80.4, 70.8, 51.4, 45.8, 26.6, 18.7. IR (KBr) 1439.3, 1488.6, 1592.9, 2172.4, 2226.4, 2938.9, 2980.9,

3437 2 cm • 2H ₂ O: C H 22 N ^C 20 ^H 20 ^N 6 ° 2 ' calc .: 63.22 5.41 21 12 Found .: 63.51 5.36 81st Beisniel 33

(trans) -N- (2-chlorophenyl) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopy * an-4 yl) guanidine

A. N-cyano-N ¹ - (2-chlorophenyl) thiourea

The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (50 mL) was slowly added with 2-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction mixture was stirred for 1 hour at room temperature and then heated to 75 ^° C. for 4 hours. The reaction mixture was cooled to room temperature, the colorless solid was filtered off and washed with ethanol to give 6.0 g of the title compound A, F. 253-255 ⁰ C.

For example, (trans) -N- (2-chlorophenyl) -N'-cyano-N- (6-cyano-3,4-dihydrodin

° dro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -guani-

The solution of the title compound A (1.26 g, 5.96 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.0 g, 4.59 mmol, prepared according to Evans et al., J. Med. Chem. (1983) 26, 1582 and J. Med. Chem. (1986) 29, 2194) in dimethylformamide (5 ml). were

Jit

treated under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.17 g, 5.96 mmol). The reaction mixture was stirred at room temperature for 2 hours and then extracted by shaking with 1 N hydrochloric acid and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was crystallized from ethyl acetate to give 1.1 g of the title compound, mp 239-24O ⁰ C.

¹ H NMR (DMSO-d ₆ ) S 9.20 (s, IH), 7.63 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 10.0 Hz, 2H) , 7.38 (m, 2H), 6.92 (d, J = 9.0 Hz, IH), 5.8 (broad s, IH), 4.91 (t, J = 9.4 & 8, 8Hz, IH), 3.68 (m, IH), 1.39, 1.17 (s, 3H each). ¹³ C NMR (DMSO-d ₆ ) S 159.3, 156.3, 132.6, 129.8, 128.0, 124.7, 119.0, 117.9, 116.7, 102.6, 80.5, 26.6, 18.6. IR (KBr) 3432.4, 2982.6, 2225.3, 2187.9, 1611.0, 1588.7, 1491.4, 1448.1,

1267 , 9 cm ". •O, 33H ₂ O: C H 68 17 N Cl ^C 20 ^H 18 ClN ₅ O ₂ calc .: 59.79 4, 79 17 , 43 8.82 Found .: 60.11 4, , 21 9.04 example 34

(trans) -N- (3-chlorophenyl) -N ^u -cyano-N- (6-cyano-3/4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) guanidine

A. N-Cyano-N '- (3-chlorophenyl) thiourea

The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (50 mL) was treated slowly with 3-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction mixture was stirred for 1 hour at room temperature and then heated to 75 ^° C. for 4 hours. The reaction mixture was cooled to room temperature, the colorless solid filtered off

 r /

and washed with ethanol to give 5.4 g of the title compound A, F. 258-260 ⁰ C.

For example, (trans) -N- (3-chlorophenyl) -N'-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran- 4-yl) guanidine

The solution of the title compound A (1.26 g, 5.96 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (3.0 g, 4.59 mmol, prepared according to Evans et al., J. Med. Chem. (1983) 26, 1582 and J. Med. Chem. (1986) 29, 2194) in dimethylformamide (5 ml). was treated under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.17 g, 5.96 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1 N hydrochloric acid and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was crystallized from ethyl acetate to give 0.9 g of the title compound, mp 243-244 ° C.

¹ H NMR (DMSO-d ₆ ) δ 9.42 (s, IH), 7.80 (d, J = 8.8 Hz, IH), 7.61 (d, J = 8.8 Hz, 2H) , 7.31 (m, 3H), 6.91 (d, J = 8.8 Hz, IH), 5.90 (broad s, IH), 4.98 (t, J = 9.4 & 8, 8Hz, IH), 3.69 (m, IH), 1.41, 1.18 (s, 3H each). ¹³ C NMR (DMSO-dg) δ 159.0, 156.3, 139.3, 133.1, 132.7, 130.5, 124.5, 124.3, 123.1, 121.9, 119 , 1, 117.9, 116.8, 102.7, 80.4, 71.0, 52.0, 26.6, 18.6, IR (KBr) 3422.4, 2980.7, 2226.5 , 2181.8, 1609.3, 1575.3, 1490.1, 1385.6, 1268.1, 1126.5 cm " ¹ .

35

^C 20 ^H 18 ^C1N 5 ° 2 •O, 08 H ₂ O: 60 C 4 H 17 N Cl About: 60 , 46 4 , 61 17 , 63 8.92 Found .: , 11 , 42 , 98 9.13

83 Example 35

(trans) -N- (4-fluorophenyl) -W-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) - guanidine

A. N-Cyano-N ^l - (4-fluorophenyl) thiourea

The suspension of monosodium cyanamide (2.1 g, 32.6 mmol) in absolute ethanol (50 mL) was slowly added with 4-fluorophenyl isothiocyanate (5.0 g, 32.6 mmol). The reaction mixture was stirred at room temperature for 1 hour and then heated at 75 ^° C. for 4 hours. The reaction mixture was cooled to room temperature, the colorless solid filtered off and washed with ethanol to give 4.1 g of title precursor A, mp> 270 ° C.

B. (trans) -N- (4-fluorophenyl) -N'-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2 _/ 2-dimethyl-2H-1-benzopyran-4 yl) guanidine

The solution of the title compound A (1.15 g, 6.0 mmol) and (trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.0 g, 4.59 mmol, prepared according to Evans et al., J. Med. Chem. (1983) 26, 1582 and J. Med.

Chem. (1986) 29, 2194) in dimethylformamide (5 ml) was treated under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 2 hours and then mi '; 1 η hydrochloric acid and ethyl acetate.

^ ® telt. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue triturated with ethyl acetate to give 0.8 g of the title compound were obtained, mp 207-208 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 9.29 (s, IH), 7.60 (m, 3H), 7.37 (m, 2H), 7.23 (m, 2H), 6.90 ( d, J = 8.8 Hz, IH), 5.90 (broad s, IH), 4.90 (t, J = 9.4 & 8.8 Hz, IH), 3.69 (m, IH) , 1.40,

1.17 (S, 3H each). ¹³ C NMR (DMSO-d _fi ) S 159.4, 156.3, 5

133.6, 132.7, 132.5, 126.7, 126.6, 124.8, 119.1, 117.9, 115.8, 115.5, 102.6, 80.4, 70, 8, 51.8, 26.6, 18.6, IR (KBr) 3412.9, 2980.5, 2226.9, 2179.4, 1611.4, 1585.5, 1509.9, 1490.6, 1385.4, 1268.2 cm " ¹

C ₂₀ H ₁₈ FN ₅ O ₂ -0.15 H ₂ O:

calc .:

Found .:

C H 18 N 5 F 2,86 4 , 83 18 , 32 4 , 01 2,89 4 80 , 29 , 84th example 36

(trans) -N- [3- (acetyloxy) -6-cyano-3 _/ 4-dihydro-2 _/ 2-dimethyl-2H-1-benzopyran-4-yl] -N ¹ -phenylguanidine

The solution of the title compound of Example 3 (2.52 g, 6.98 mmol) and acetic anhydride (1.0 g, 9.8 mmol) in pyridine (25 mL) was stirred at room temperature for 60 hours. The crude reaction mixture was extracted by shaking with ethyl acetate and 5% aqueous hydrochloric acid. The organic layer was washed with distilled water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 2.97 g of a white solid. The crude reaction product was crystallized from ethanol in two batches, with 2.24 g of the title compound as the starting material.

° ner white solid were obtained, F. 239-240 ⁰ C

¹ H NMR (DMSO-d ₍ ) δ 9.36 (s, IH), 7.63 (m, 3H), 7.35 (m, 2H), 7.20 (m, 3H), 6.97 ( d, J = 8.80 Hz, IH), 5.23 (m, 2H), 2.17 (S, 3H), 1.34 (S, 3H), 1.25 (s, 3H). ¹³ C NMR (DMSO-dg) <S 169.69, 158.69, 155.75, 136.95, 132.94, 132.66, 129.03,

125.28, 124.25, 123.79, 118.86, 118.09, 116.62, 103.31, 78.43, 72.07, 49.49, 25.85, 20.67, 19, 54th

^C 22 ^H 21 ^N 5 ° 3 ^: 65 C H 37 17 N calc .: 65 50 5.25 17 , 36 gef. : , 54 5.27 , 36 example

(3S-trans) -N ^II -cyano-N- (6-cyano-3/4-dihydro-3-hydroxy-2 _/ 2-dimethyl-2H-1-benzopyran-4-yl) -N · - (4 fluorophenyl) guanidine

The solution of N-cyano-N ¹ - (4-fluorophenyl) -thiourea (1.15 g, 6.0 mmol, prepared according to Example 35, part A) and (3S-trans) -4-amino-3,4 -dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.0g, 4.59mmol, Compound of Example 20, Part B) in dimethylformamide (5ml)

* 5 under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 2 hours and then extracted by shaking with 1 N hydrochloric acid and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 20% hexane in ethyl acetate to give 0.55 g of a colorless solid. This solid was triturated with diethyl ether to give 0.45 g of the title compound were obtained, mp 218-219 ⁰ C. ¹ H NMR _(DMSO-d6) <S 9.29 (s, IH), 7.60 (m , 3H), 7.37 (m, 2H), 7.23 (m, 2H), 6.90 (d, J = 8.8 Hz, IH), 5.90 (broad s, IH), 4, 90 (t, J = 9.4 & 8.8 Hz, IH), 3.69 (m, IH), 1.40, 1.17 (s, 3H each); ¹³ C NMR (DMSO-d ₆ ) 159.4, 156.3, 133.6, 132.7, 132.5, 126.7, 126.6, 124.8, 119.1, 117.9, 115 , 8, 115.5, 102.6, 80.4, 70.8, 51.8, 26.6, 18.6; IR (KBr) 3412.9, 2980.5, 2226.9, 2179.4, 1611.4, 1585.5, 1509.9, 1490.6, 1385.4, 1268.2 cm ^-1 '[a _D ] ²⁵ = -33.1 ° (c = 0.483, MeOH).

jih

^C 20 ^H 18 ^FN 5 ° 2 ^: 63 C H N 46 5 F calc .: 63 , 32 4.78 18 08 4 , 01 gef. : , 08 4.94 18 , 88 example 38

(3S-trans) -N- (4-chlorophenyl) -N ⁿ -cyano-N ^l - (6-cyano-3 _/ 4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4 yl) guanidine

The solution of N-cyano-N '- (4-chlorophenyl) -thiourea (1.26 g, 5.96 mmol, prepared according to Example 31, part A) and (3S-trans) -4-amino-3,4 -dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.0 g, 4.59 mmol, Compound of Example 20, Part B) in dimethylformamide (5 mL) under argon treated with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.14 g, 5.96 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1 N hydrochloric acid and ethyl acetate. The aqueous phase was reconstituted with acetic acid

² ^ ethyl ester and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography eluting with a mixture of acetic acid.

² ^ acid ethyl ester / hexane (8: 2) to give 0.6 g of a solid. This solid was triturated with diethyl ether to give 0.48 g of the title compound were obtained, mp 170-172 ⁰ C.

¹ H NMR (DMSO-d ₆ ) S 9.43 (s, IH), 7.68 (m, 3H), 7.45 (m, 4H), 6.95 (d, J = 8.8 Hz, IH), 5.99 (broad s, IH), 4.98 (t, J = 9.4 & 8.8 Hz, IH), 3.79 (m, IH), 1.50, 1.27 ( s, 3H each); ¹³ C NMR (DMSO-d ₆ ) 159.1, 156.2, 136.5, 132.6, 132.5, 128.8, 125.5, 124.6, 119.0, 117.8, 116 , 8, 102, 6, 80, 4, 70, 9, 51, 9, 26, 5, 18, 5; IR (KBr) 3400.7, 2226.0, 2181.6, 1606.8, 1575.9, 1491.1, 1267.3 cm ^-1 .

[a _D ] ²⁵ 0 -32.9 ° [r = 0.492, MeOH).

C ₂₀ H ₁₈ ClN ₅ O ₂ •O, 17 H ₂ O: C 4 H 17 N 8th Cl calc .: 60.21 4 , 64 17 , 55 8th , 89 Found .: 60.49 39 80 , 27 90 example

(3S-trans) -N- (3-chlorophenyl) -N'-syano-Ν '- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyranoyl) 4-yl) guanidine

The solution of N-cyano-N ^! - (3-chlorophenyl) thiourea (1.26 g, 5.96 mmol, prepared according to Example 34, part A) and (3S-trans) -4- <amino-3,4-dihydro-3-hydroxy-2 , 2-Dimethyl-2H-1-benzopyran-6-carbonitrile (1.0g, 4.59mmol, Compound of Example 20, Part B) in dimethylformamide (5ml) was extracted under argon with 1- (3-dimethylaminopropyl). 2-ethylcarbodiimide hydrochloride (1.17 g, 5.96 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with 1 N hydrochloric acid and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 20% hexane in ethyl acetate to give 1.0 g of a colorless solid. The solid was auskristaliisiert from ethyl acetate to give 0.36 g of the title compound were obtained, mp 239-240 ⁰ C.

¹ H NMR (DMSO-d ₆ ) S 9.42 (s, IH), 7.80 (d, J = 8.8 Hz, IH), 7.61 (d, J = 8.8 Hz, 2H) , 7.31 (m, 3H), 6.91 (d, J = 8.8 Hz, IH), 5.90 (broad s, IH), 4.98 (t, J = 9.4 & 8, 8Hz, IH), 3.69 (m, IH), 1.41, 1.18 (s, 3H each); ¹³ C NMR (DMSO-d ₆ ) 159.0, 156.3, 139.3, 133.1, 132.7, 130.5, 124.5, 124.3,

123.1, 121.9, 119.1, 117.9, 116.8, 102.7, 80.4, 71.0, 52.0, 26.6, 18.6; IR (KBr) 3422.4, 2980.7, 2226.5, 2181.8, 1609.3,

1575.3, 1490.1, 1385.6, 1268.1, 1126.5 cm ^-1 . [A _D ] ²⁵ 0 -45.8 (c = 0.45, dimethylformamide) C ₂₀ H ₁₈ ClN ₅ O ₂ .0.06 H ₂ O:

About:

gef. :

C 4 H N 8th Cl 60.52 4 60 17.65 9 , 93 60.25 40 , 34 17.92 , 29th example

trans -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ¹ - [4- (phenylmethoxy) phenyl) guanidine

A. N-Cyano-N ¹ - (4-phenylmethoxyphenyl) thiourea

The suspension of monosodium cyanamide (1.33 g, 20.7 mmol) in absolute ethanol (50 mL) was slowly added with 4-phenylmethoxyphenyl isothiocyanate (5.0 g, 20.7 mmol). The reaction mixture was stirred for 1 hour at room temperature and

on ^u then heated to 75 ° C for 4 hours. The reaction mixture was cooled to room temperature, the colorless solid filtered off and washed with ethanol to give 4.0 g of the title compound A, mp> 270 ° C.

Trans-W-cyano-N-fe-cyano-S-dihydro-a-hydroxy ^^ -dimethyl-2H-1-benzopyran-4-yl) -N ¹ - [4- (phenylmethoxy) -phenyl ) guanidine

The solution of title compound A (1.68 g, 6.0 mmol) and ^ow trans-4-amino-3,4-d: hyrro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6 carbonitrile. (1.0 g, 4.59 mmol, prepared according to Evans et al., J. Med. Chem. (1983) 26, 1582 and J. Med. Chem. (1986) 29, 2194) in dimethylformamide (5 ml). was treated under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted with 10% citric acid and ethyl acetate.

J9H

shaken and the resulting solid separated. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue with the solid obtained above are combined and ester crystallized from hot Essigsäureethy! To afford the title compound (1.1 g) was obtained as a colorless solid, m.p. 229-230 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 9.13 (s, IH), 7.62 (m, 2H), 7.37 (m, 6H), 7.24 (d, J = 8.8 Hz, 2H), 7.0 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.2 Hz, IH), 5.85 (broad s, IH), 5.1 (s, 2H ), 4.90 (t, J = 9.0 Hz, IH), 3.69 (m, IH), 1.40, 1.16 (s, 3H each); ¹³ C NMR (DMSO-d ₆ ) 159.6, 156.3, 137.0, 132.6, 132.4, 128.5,

127.9, 127.7, 126.6, 125.0, 119.1, 117.8, 117.3, 115.2, 102.6, 80.4, 70.6, 69.4, 51, 6, 26, 6, 18, 6; IR (KBr) 2978.0, 2936.0, 2226.3, 2180.7, 1610.0, 1581.3, 1510.9, 1489.7,

1267.5, 1,238.5 cm ". C H N 79 ^C 27 ^H 25 ^N f jO-j · 0, 34 H ₂ O: 68.47 5.46 14 71 calc .: 68.55 5.34 14 gef. : example 41

^2δ trans ^-N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyrano-4-yl) -N ¹ - (4-hydroxyphenyl) guanidine

A solution of the title compound of Example 40 (0.7 g, 1.5 mmol) in ethanol (70 ml) was treated with 10% palladium on

^Oyj carbon (0.1 g) was added. The mixture was then treated in a receiver with hydrogen and heated to 6O ⁰ C for 2 hours. The reaction mixture was filtered through a pad of celite, the filtrate washed with ethanol and concentrated under reduced pressure to give the title compound

as a colorless solid (0.5 g). F. 171-173 ° C.

¹ H NMR (DMSO-d ₆ ) S 9.40 (s, IH); 9.03 (s, IH), 7.58 (d, J = 8.2 Hz, IH), 7.51 (s, 2H), 7.2 (s, IH), 7.11 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.2 Hz, IH), 6.73 (d, J = 8.8 Hz, 2H), 5.85 (broad s, IH) , 4.87 (t, J = 9.0 Hz, IH), 3.71 (m, IH), 1.38, 1.15 (s, 3H each); ¹³ C NMR (DMSO-dg) 159.6, 156.3, 132.6, 132.4, 127.0, 126.6, 119.1, 117.8, 117.3, 115.6, 102, 6, 80.4, 79.4, 70.6, 51.6, 26.7, 18.6; IR (KBr) 3485.6, 2986.0, 2941.6, 2226.0, 1585.6, 1514.2, 1491.1, 1307.8, 1271.2, 1128.4 cm ^-1

C ²⁰ H ₁₉ N ₅ O ₃ 0,4 0.4 H ₂ O:

H ₂ O: C H 18 N About: 62.46 5.19 17 , 21 gef. : 62.71 5.17 96 example 42

(? 6-acetyl-3,4-dihydro-3-hydroxy. -, 2-dimethyl-2H-lbenzopyran-4-yl) trans-N- ⁿ -N-cyano-N'-phenylguanidine

The solution of N-cyano-N-phenyi thiourea (0.98 g, 5.5 mmol, Compound of Example 3, Part A) and 6-acetyl-3,4-dihydro-2,2-dimethyl-3 -hydroxy-4-amino-2H-1-benzopyran (1.0 g, 4.25 mmol, prepared according to Evans et al., J. Med. Chem. (1983) 26, 1582 and J. Med. Chem. 1986) 29, 2194) in dimethylformamide (6 ml) was treated under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.1 g, 5.5 mmol). The reaction mixture was stirred at room temperature for 2 hours and then extracted by shaking with 10% citric acid and ethyl acetate. The aqueous phase was extracted again with ethyl acetate and the combined

³ ^ Ned extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue crystallized from ethyl acetate to obtain 0.34 g of the title compound were obtained, mp 182-184 ⁰ C.

¹ H NMR (DMSO-d ₆ ) δ 9.45 (s, IH), 7.82 (m, 3H), 7.44 (s, 3H), 7.25 (s, IH), 6.96 ( d, J = 9.0 Hz, IH), 6.0 (s, IH), 5.1 (m,

IH), 4.15 (m, IH), 3.8 (s, IH), 2.61 (s, 3H), 1.52 (s, 3H), 1.29 (s, 3H); ¹³ C NMR (CDCl ₃ ) S 196.2, 159.3, 156.6, 137.6, 129.7, 129.1, 128.4, 124.7, 123.5, 123.3, 117.2 , 116.6, 80.0, 71.2, 52.3, 26.7, 26.3, 18.6; IR (KBr) 3412.3, 2978.3,

, 2935.8, 2179.7, 1670.5, 1602.9, 1577.9, 1493.0, 1359.9, 1271.2, 1126.5 cm ^-1 .

C ₂₁ H ₂₂ N ₄ O ₃ -0.57 H ₂ O: CHN

calculated: 64.89 6.00 14.41

F .: 65.23 6.11 13.98 10

Example 43

(3S-trans) -N- (3/4-dichlorophenyl) -N ^M -cyano-N • - (6-cyano-3 , A- dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran -4-yl) guanidine

A. N-cyano-N · (3,4-dichlorophenyl) thiourea

The suspension of monosodium cyanamide (1.6 g, 24.5 mmol) in absolute ethanol (50 mL) was slowly added with 3,4-dichlorophenylisothiocyanate (5.0 g, 24.5 mmol). The reaction mixture was stirred for 1 hour at room temperature and then heated to 75 ^° C. for 4 hours. The reaction mixture was cooled to room temperature, the colorless solid filtered off and washed with ethanol to give 5.0 g of the title compound A as a colorless solid.

B.

3 _/ 4-dihydro-3-hydroxy-2 _/ 2-dimethyl-2H-1-benzopyran-4-yl) -guanidine

The solution of the title compound A (1.47 g, 6.0 mmol) and (3S-trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6 carbonitrile (1.0 g, 4.6 mmol, Compound of Example 20, Part B) in dimethylformamide (10 mL) was treated under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1.13 g, 6.0 mmol). The reaction

The mixture was stirred for 2 hours at room temperature and then extracted by shaking with a buffer of pH 4 and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water (4 × 200 ml), sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography (ethyl acetate: hexane / 7: 3) to give 0.6 g of a colorless solid. The solid was triturated with diethyl ether to give 0.5 g of the title compound were obtained, mp 168-170 ⁰ C.

¹ H NMR _(CDCl3) δ 9.30 (s, IH), 7.64 (s, IH), 7.58 (d, J = 2.4 Hz, IH), 7.40 (m, 2H) , 7.30 (dd, J = 2.3 & 2.9, IH), 6.85 (d, J = 8.8 Hz, IH), 4.97 (m, IH), 3.70 (i.e. , J = 10.0 Hz, IH), 1.49, 1.26 (s, 3H each); ¹³ C NMR (CDCl ₃₎ 158.6, 155.8, 136.4, 131.9, 131.4, 129.7, 118.1, 117.3, 102.6, 79.6, 51.8 , 25.8, 17.8; IR (KBr) 3398, 2980, 2225, 2183, 1610, 1581, 1489, 1371 cm ^-1 . [A _D ] ²⁵ = -35.37 ° (c = 0.458,

²⁰ dimethylformamide).

C ₂₀ H ₁₇ Cl ₂ N ₅ O ₂ -0.37 H ₂ O:

ber .: gef .:

(3S-trans) ^-N-cyano-N N- _{(6-cyano-3/4-dihydro-3-hydroxy-2/2-dimethyl-2H-l-benzopyran-4-yl)} -N * - [4 - (trifluoromethyl) -phenyl) -guanidine

A. N-Cyano-N ¹ - (4-trifluoromethylphenyl) thiourea

The suspension of monosodium cyanamide (0.63 g, 9.8 mmol) in absolute ethanol (50 mL) was slowly added with 4-trifluoromethylphenyl isothiocyanate (2.0 g, 9.8 mmol). The reaction mixture was stirred for 1 hour at room temperature and then heated to 75 ^° C. for 4 hours. The reaction mixture was

C H 09 16 N Cl 54.97 4, 04 15 , 02 16.22 55.39 4, 60 15.97 example 44

cooled to room temperature, the colorless solid filtered off and washed with ethanol to give 2.0 g of the title compound as a colorless solid.

B. (3S-trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -N ^L - [4- (trifluoromethyl) phenyl)] - guanidine

The solution of the title compound A (1.3 g, 5.3 mmol) and (3S-trans) -4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-ben-

Zopyran-6-carbonitrile (0.83 g, 3.8 mmol, prepared according to Example 20, Part B) in dimethylformamide (10 mL) was purified under argon with 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (1, 1 g, 5.7 mmol). The reaction mixture was stirred for 2 hours at room temperature and then extracted by shaking with a buffer of pH 4 and ethyl acetate. The aqueous phase was extracted again with ethyl acetate and the combined extracts were washed with water (4 × 200 ml), sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography eluting with a mixture of ethyl acetate / hexane (7: 3). The solid was triturated with diethyl ether to give 0.45 g of the title compound were obtained, mp 209-210 ⁰ C.

¹ H NMR _(CDCl3) δ 9.41 (s, IH), 7.60 (m, 6H), 6.85 (d, J = 8.8 Hz, IH), 4.99 (m, IH) , 3.74 (d, J = 9.4 Hz, IH), 1.50, 1.28 (S, 3H each); ¹³ C NMR (CDCl ₃ ) 158.7, 156.0, 140.4, 132.1, 125.5, 123.9, 121.9, 118.3, 117.5, 102.8, 79.8 , 52.1, 25.9, 18.0; IR (KBr) 3403, 2225, 2184, 1588, 1491, 1325, 1126, 1069 cm " ¹

[a _D ] ²⁵ = -40.2 (C = 0.567, MeOH).

^C 21 ^H 18 ^F 3 ^N 5 ° 2 ^: CHNF

Calc .: 58.74 4.23 16.31 13.27 Found: 59.15 4.16 16.18 13.53.

M 9

GERMAN PATENT OFFICE

E η d

the act

A 9609

Claims (31)

Patent claims 1. A process for the preparation of compounds of the general
NEN formula I F ¹ in which a, b and c are each carbon atoms or one of the radicals a, b and c can have the meaning nitrogen or -NO- and the remaining radicals are carbon atoms;
R _{1 is} a radical of the formulas R ₉ - / = NCN; Il means; R _{0 is} hydrogen, hydroxyl or the radical of the formula -OCCHo Il ³ o means; R ₃ and R _{4 are} each independently hydrogen, alkyl or arylalkyl, or R ₃ and R _{4 taken} together with the carbon atom to which they are attached form a 5- to 7-membered carbocyclic ring;
R ₅ is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, cycloalkylalkyl, -CN, -NO ₂ , -COR, COOR, -CONHR, -CONR ₂ , -CF ₃ , S-alkyl, -SOalkyl, - SO ₂ alkyl, (o-alkyi) ₂ , - ° ~ L 4-B, Ϊ15 Halogen, amino, substituted amino, Ο-alkyl, OCF ₃ , OCH ₂ CF ₃ , -o-alkyl, -OCONR-alkyl, -NRCO-alkyl, -NRCOO-alkyl and -NRCONR ₂ , wherein R in the each of the above groups is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl) alkyl; R _{6 is selected} from H, alkyl, OH, O-alkyl, amino, substituted amino, CN and NO ₂ ; R ₇ and R _{8 are} each independently selected from hydrogen, alkyl, alkenyl, aryl, (heterocyclo) alkyl, heterocyclo, arylalkyl, cycloalkyl, (cycloalkyl) alkyl and substituted alkyl wherein the substituents include alkoxy, alkylthio and substituted amino or R ₇ and R ₈ together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl or Form 4-arylalkyl-l-piperazinyl, wherein the individual groups formed in this way may be substituted by alkyl, alkoxy, alkylthio, halogen or trifluoromethyl;
R ₉ and R _{10 are selected} from hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl; and η is 1, 2 or 3;
characterized in that (A) for the preparation of compounds of formula I in which R _{1 is} the meaning R ₉ - Has,
(a) a thiourea of the general formula II X f * NC-l / (II) with an amine of general formula III (III) R ₅ b in the presence of a carbodiimide and an acid source in an organic solvent; (b) a thiourea of the general formula VI (VI) with monosodium cyanamide in the presence of a carbodiimide in an organic solvent; or (c) a compound of general formula VII R ₉ -N (VII) with an amine of formula VIII R ₇ R ₈ NH (VIII) in a polar solvent; or (B) (a) for the preparation of compounds of the formula I in which R _{1 is} a radical of the formula • 10 J.N. = NCN means a compound of general formula IX Rio (IX) reacted with mercury (II) acetate in an alcoholic solvent; or (B) for the preparation of compounds of general formula I in which R _{1 is} a radical of the formula means a diamine of general formula X. NH reacted with diphenyl cyanocarbonimidate in an alcoholic solvent; or (C) for the preparation of compounds in which R _{2 has} the meaning OCO-alkyl, an alcohol of the formula I, in which R _{2 is} OH, with an acid chloride of the general formula XIV A, (XIV) in the presence of a zeolene catalyst. 2. The method according to claim 1, characterized in that one produces compounds in which
a is nitrogen or -CR ₅ ;
b and c are each -CH-; R _{1 is} a radical of the formulas Vncn R ₉ - / or means; = NCN; R _{2 is} hydroxy or OCO-alkyl; R ₃ and R _{4 are} each alkyl; R _{5 represents} an electron-withdrawing group; R _{6 is} hydrogen, alkyl, O-alkyl or amino; R _{7 is} hydrogen, alkyl, aryl or arylalkyl, Rg is hydrogen; R _{9 is} hydrogen or alkyl; R _{10 is} hydrogen; and η is 1 or 2. 3. Process according to Claim 1, characterized in that compounds are prepared in which a denotes nitrogen or -CR ₅ ; b and c are each -CH-; R _{2 is} trans-hydroxy; R ₃ and R _{4 are} each methyl; R _{5 is} -CN or -NO ₂ ; R _{6 is} hydrogen; R _{7 is} hydrogen, methyl, ethyl, phenyl or phenylmethyl; Rg is hydrogen; Rg is hydrogen; R _{10 is} hydrogen; and η has the value 1. 4. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran- 4-yl) -N · - (1,1-dimethylpropyl) guanidine. 5. The method according to claim 1, characterized in da / 3 man (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l- benzopyran-4-yl) -N · ethylguanidine. 6. The method according to claim 1, characterized in that one (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy _8th / 9ΗΪ7Ϊ 2 , 2-dimethyl-2H-1-benzopyran-4-yl) -N'-phenylguanidine. 7. The method according to claim l, characterized in that (trans) -N ^M- cyano-N- (3,4-dihydric-3-hydroxy-2,2-dimethyl-6-nitro-2H-l-benzopyran- 4-yl) -N'-ethylguanidine. 8. The method according to claim 1, characterized in that (trans) -3,4-dihydro-3-hydroxy-2,2-dimethyl-4- [2- (cyanoimino) -1-pyrrolidinyl] ^ Hl-benzopyran- produces δ-carbonitrile. 9. The method according to claim 1, characterized in that one comprises (trans) -N "-cyano-Ν- (3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-pyrano [3,2-c ] pyridin-4-yl) -phenylguanidine. 10. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran- 4-yl) -1-pyrrolidine-carboximidamide. 11. The method according to claim 1, characterized in that (trans) -N "-cyano-N-ce-cyano-S ^ dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-4- yl) -N'-ethyl-N-methylguanidine. 12. The method according to claim I _1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran- 4-yl) -N · - [2- (dimethylamino) ethyl] guanidine. 13. The method according to claim 1, characterized in that (trans) -4 - [[(cyanoimino) - (1-pyrrolidinyl) methyl] amino] -3,4-dihydroxy-2,2-dimethyl-2H- l-benzopyran-6-carbonitrile produces. 14. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran- 4-yl) -N · -methylguanidin
manufactures. 15. The method according to claim 1, characterized in that (trans) -4 - [(cyanoimino) - [[4- (phenylmethyl) -1-piperazinyl] methyl] amino] -3,4-dihydro-3 hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile. 16. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydric-3-hydroxy-2,2-dichloro-2H-l-benzopyran- 4-yl) -guanidine. 17. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran- 4-yl) -N '- (methyl-thyl) -guanidine. 18. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran- 4-yl) -N'-dimethylguanidine
manufactures. 19. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl ~ 2H-l-benzopyran- 4-yl) -N ¹ -phenylmethylguanidine. 20. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-bem: opyran-4-yl) -N · - [2- [(phenylmethyl) methyl] amino] ethyl] guanidine. 21. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy ίο 2,2-dimethyl-2H-1-benzopyran-4-yl) -N - (2-methoxyethyl) guanidine. 22. A method according to claim 1, characterized in that (3S-trans) -M'-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l- benzopyran-4-yl) -N'-phenylguanidine. 23. The method according to claim 1, characterized in that (3R-trans) -HF-cyano-N-IE-cyano-S ^ dihydro-S-hydroxy-2,2-dimethyl-2H-l-benzopyran-4 -yl) -N'-phenylguanidine. 24. The method according to claim 1, characterized in that one comprises (trans) -4- [2- (cyanoimino) -tetrahydro-l (2H) -pyrimidinyl] -3,4-dihydro-3-hydroxy-2,2-dimethyl -2H-1-benzopyran-6-carbonitrile. 25. The method according to claim 1, characterized in that one produces the compound of the following structural formula: 26. The method according to claim l, characterized in that (trans) -N »-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran- 4-yl) -N · - (2-methoxyethyl) guanidine. 27. The method according to claim l ', characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran -4-yl) -N · - (4-pyridinylmethyl) guanidine. 28. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran- 4-yl) -N · - (3-pyridinylmethyl) guanidine. 29. The method according to claim 1, characterized in that (trans) -N '^ cyano-N-he-ethynyl-S ^ dihydro-S-hydroxy-2,2-dimethyl-2H-l-benzopyran-4- yl) -N · -phenylguanidin
manufactures. 30. The method according to claim 1, characterized in that (trans) -N "-cyano-N- (3,4-dihydro-6- (phenylethynyl) -2H-l-benzopyran-4-yl) -N'- produces phenylguanidine. 31. The method of claim 1 _; characterized in that compounds of general formula I are prepared (D -R ₂ -R ₃ R4 in which a, b and c are each carbon atoms or one of the radicals a, b and c can have the meaning nitrogen or -NO- and the remaining radicals are carbon atoms;
R _{1 is} a radical of the formula or < "Ν 12 Ji 9 H means; R _{2 is} a hydrogen, hydroxyl or the radical of the formula 0 means; R ₃ and R _{4 are} each independently hydrogen, alkyl or arylalkyl, or R ₃ and R _{4 taken} together with the carbon atom to which they are attached form a 5- to 7-membered carbocyclic ring;
R ₅ is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, cycloalkylalkyl, -CN, -NO ₂ , -COR, -COOR, -CONHR, -CONR ₂ , -CF ₃ , S-alkyl, -SOalkyl, -SO ₃ alkyl, halogen, amino, substituted amino, O-alkyl, -OCO-alkyl, -OCONR-alkyl, -NRCO-alkyl, -NRCOO-alkyl and -NRCONR ₂ , wherein R in the above groups each represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl) alkyl;
R _{6 is selected} from H, alkyl, OH, O-alkyl, amino, substituted amino, CN and NO ₂ ; R ₇ and R _{8 are} each independently selected from hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl and cycloalkylalkyl, or R ₇ and R 1 together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, Form 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl or 4-arylalkyl-1-piperazinyl, the individual groups thus formed being alkyl, alkoxy, alkylthio, halo or trifluoromethyl may be substituted; R ₉ and R _{10 are selected} from hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl; and η is 1, 2 or 3.