EP0413807A1 - Acylated polyamines and applications thereof as vegetable growth regulators - Google Patents

Abstract

The present invention relates to the compounds of general formula (I) in which, R1 represents: either an ArO- radical in which Ar represents an aryl, heteroaryl or heterocyclic radical, or an aryl, polyaryl or heterocyclic radical. W represents: either a radical (CH2) n1, or a radical (CH2) n2NY (CH2) n3, Y representing a hydrogen atom or an alkyl, aryl, arylalkyl, CO2 alkyl, COR2 radical in which the radical R2 represents a alkyl, alkynyl, or an aryl or arylalkyl or heterocyclic radical. Z represents: either a hydrogen atom, or a radical (a), or a radical (b) in which R'2 represents an alkyl, arylalkyl radical, or an alkyl CO2 radical, or an arylalkyl CO2 radical, or a radical COR''2 in which R''2 can take one of the values indicated above for R2, either a radical -CH2R3 in which R3 represents an aryl, substituted heteroaryl, heterocyclic radical, or can take the values indicated above above for R1, that is to say a radical -COCH2R'3 in which R'3 can take one of the values indicated above for R3. The products of formula (I) have regulatory properties for plant growth.

Description

 Application as growth promoters for plants, acylated polyamines.

The present invention relates to the application, as plant growth regulators, of acylated polyamines.

The subject of the invention is, as plant growth regulators, the compounds of formula (I):

in which, R. represents: - either an ArO radical - in which Ar represents an aryl radical containing up to 14 optionally substituted carbon atoms or an optionally substituted heteroaryl radical, or an optionally substituted heterocyclic radical,

- Either an aryl or polyaryl radical, condensed or not or an optionally substituted heterocyclic radical.

W represents:

- or a radical (CH ₂ ) n .. in which n. represents an integer that can vary from 2 to 6,

- or a radical (CH ₂ ) n ₂ NY (CH ₂ ) n ₃ in which n ₂ and n ₃ identical or different represent an integer which can vary from 2 to 6 and Y represents a hydrogen atom or an alkyl radical containing up to 12 carbon atoms or an aryl radical containing up to 14 optionally substituted carbon atoms or an arylalkyl radical containing up to 18 carbon atoms optionally substituted, or a C0 ₂ alkyl radical in which the radical alkyl contains up to 12 carbon atoms, or a C0R ₂ radical in which the radical R ₂ represents an alkyl, alkenyl or alkyyl radical containing up to 12 carbon atoms or an aryl radical containing up to 14 carbon atoms carbon or an arylalkyl radical containing up to 18 optionally substituted carbon atoms or a heterocyclic radical optionally substituted and

LACING Z represents:

- either a hydrogen atom,

- or a radical -ç = NH

- either a radical in which R * ₂ represents an alkyl radical containing up to 12 carbon atoms, or an arylalkyl radical containing up to 18 carbon atoms, - or a C0 ₂ -alkyl radical in which the alkyl radical contains up to 12 carbon atoms,

- or a C0 ₂ -arylalkyl radical in which the aryl¬ alkyl radical contains up to 18 carbon atoms,

- either a COR " ₂ radical in which R" ₂ can take one of the values indicated above for R ₂ ,

- either a radical -CH ₂ R ₃ in which R ₃ represents an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic radical or can take the values indicated above for R-, - or a radical -COCH ₂ R * ₃ in which R ' ₃ can take one of the values indicated above for R ₃ , provided that Z does not represent a hydrogen atom, if W represents a radical (CH ₂ ) ₃ and R represents a radical 2,4-dichlorophenoxy as well as the addition salts with organic or mineral acids of the compounds of formula (I). The products of formula (I) are described and claimed for their fungicidal in general application in the European patent n ^β of deman¬ 89.403614.4 filed December 22, 1989. Among the addition salts with acids, may be mentioned those formed with mineral acids such as hydrochloric, hydrous, hydroiodic, nitric or phosphoric acids, or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fu aric acid, succinic, tartaric, citric, oxalic, glycolic, aspartic, alkanesulfonic such as methane or ethane sulfonic acids, or arylsulfonic such as benzene or paratoluene sulfonic acids.

REPLACEMENT SHEET In the definition of the different substituents:

aryl preferably represents a phenyl radical,

polyaryl preferably represents a naphthyl radical or a biphenyl radical, alkyl preferably represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl or tert-butyl radical,

- alkenyl preferably represents a vinyl, allyl or 1,1-dimethylallyl radical. - alkynyl preferably represents an ethynyl or propynyl radical.

- The heterocyclic radicals concerned are preferably the pyridyl, furanyl, thiophenyl, indolyl, coumarinyl, oxazolyl, thiazolyl or a radical 7- (3,7-dihydro 1,3-dimethyl 2,6-dioxo) 1H-purinyl .

The arylalkyl radicals of the radicals W and Z, when they are substituted, are preferably substituted by hydroxyl radicals, halogen atoms such as for example chlorine or bromine atoms, CF ₃ radicals, alkyloxy radicals containing up to 4 carbon atoms, for example the methoxy radical.

The products of formula (I) can be prepared according to a preparation process characterized in that 1 * an acid of formula (II) is subjected:

R ₁ CH ₂ COOH (II)

in which R- _^ retains its previous meaning or a functional derivative of this acid, on the action of a polyamine of formula (III):

NH ₂ -W-NH-Z (III)

in which W and Z retain the same meaning as above, to obtain the corresponding compound of formula (I), which is subjected if desired in the case where Z is a hydrogen atom to the action of a functionalizing agent has functioned, then submits if desired the compound of

REPLACEMENT SHEET formula (I) obtained by the action of an acid to form its salt.

This direct acylation of the innate NH ₂ (W) NHZ by the acid R- ^ CI ^ COOH, can be done directly by heating or by activation of the acid function using for example dicy-clohexylσarbodiimide, N, N'-carbonyldiimidazole or diethylcyanophosphonate or also via the acid derivatives according to the reaction:

O R- ^ OL + NI ^ -fWJ-NH-Z -> R ₁ -CH ₂ -C-NH () NH-Z

L can take one of the following values: L = Cl or OCOR ¹ L =

See on this subject the works of:

J. March "Advanced. Organic Che istery" Sec. Ed p 384

Albertson Org. React. .12., 205-218 (1962) Klausner, Bodansky, Synthesis 453 (1972)

Paul, Anderson, J. Am. Che. Soc. 82., 4596, (1960), Tetrahedron Lett. 1595 (1973), Tetrahedron 3_2, 2211 (1976)

REPLACEMENT SHEET Beck it "Che istery of A ides" Ed. Zabicky 73-185 (1970) or the following articles:

Che. Rev 52, 237-416 (1953) Che. Pharm. Bull (1982) 0, 4242 Bull. Chi. Soc. Fr (1982) II, 167 Tetrahedron Lett. (1980) 21, 841 Tetrahedron Lett. (1985) 2j6, 1977 Synthesis (1982) 933 Chem. Lett. (1985) 123 Heterocycles (1988) 22, 323 Chem. Lett. (1987) 879-882. The compounds of formula (III) are known generally and can be prepared in a conventional manner according to the methods described by Green Protective Groups in Organic Synthesis Wiley Ed, Hoppe Seyler's Physiol. Chem. 357, 1651

(1976), Bergeron and Ail Synthesis 1982, 689, Bergeron and Ail J. Org. Chem. (49) 2997, At ell and Coll Synthesis 1984 (1033). Certain products of formula (III) in which W represents the radical - (CH ₂ ) n ₄ NH (CH ₂ ) n ₅ - in which n ₄ and n ₅ are defined as above as well as those for which

Z = CH = N-COOR ' ₂ and W = (CH ₂ ) _n with n varying from 2 to 6, are

NHCOOR ' ₂ products whose preparation is given below, in the experimental part. The products of formula (I) in which R- is a radiol ArO- can be prepared according to a process characterized in that a compound of formula (VI) is subjected:

ArOH (VI)

to the action of a compound of formula:

Hal-CH ₂ -CO-NH- -NHZ (VII)

in which W and Z retain their previous meaning and Hal represents a halogen atom to obtain the compound of formula (I _β ) corresponding:

REPLACEMENT SHEET Ar-0-CH ₂ -C-NH- -NHZ (I _β )

which is subjected if desired to the action of an acid to form its salt.

The compounds of formula (VII) used as starting materials can be prepared according to the following reaction scheme:

Their preparation is given below in the experimental part.

Two particular products entering into the general formula (I), namely the products of Examples 24 and 27 are new. These are N - [(4-hydroxy 3-methoxy phenoxy) acetyl] 1,4-diamino butane and N - [(2-methyl 6-indolyloxy) acetyl] 1,4-diamino butane and their addition salts with organic or mineral acids.

A more particular subject of the invention is, as plant growth regulators, the compounds of formula (I) in which the aryl, heteroaryl, arylalkyl and heterocyclic radicals are optionally substituted by one or more substituents chosen from the group consisting of hydroxyl radicals, halogen atoms, alkyl, alkenyl and alkynyl radicals containing up to 14 carbon atoms, CF ₃ radicals, OR " ₃ radicals in which R" ₃ represents an alkyl radical containing up to 12 carbon atoms or an arylalkyl radical containing up to 18 carbon atoms, the COalkyl, Si (alkyl) ₃ , SO ₂ alkyl radicals in which the alkyl radical contains up to 12

REPLACEMENT SHEET carbon atoms, and the S0 ₂ aryl radicals in which the aryl radical contains up to 14 carbon atoms, the different radicals being able to form, with the atoms to which they are linked, rings 0-CH ₂ ~ 0, thus as their addition salts with organic or mineral acids.

A subject of the invention is in particular, as plant growth regulators, the compounds of formula (I) in which W represents a radical (CH ₂ ) ₃ ; (CH ₂ ) ₄ or (CH ₂ ) ₅ , or a radical (CH ₂ ) n ₄ NH (CH ₂ ) n-. in which n ₄ and n _{5, which are} identical or different, represent the numbers 3, 4 or 5 as well as their addition salts with organic or mineral acids.

The subject of the invention is in particular as plant growth regulators, the compounds of formula (I) in which Z represents a hydrogen atom, or a C0 ₂ alkyl radical in which the alkyl radical contains up to 12 atoms of carbon or a radical

R * ₂ keeping the same meaning as above as well as their addition salts with organic or mineral acids. The subject of the invention is in particular, as plant growth regulators, the compounds of formula (I) in which R represents an ArO- radical in which Ar represents an optionally substituted aryl radical, for example those in which Ar represents the radical:

as well as their addition salts with organic or mineral acids.

The subject of the invention is in particular, as plant growth regulators, the compounds of formula (I) in which ^ represents a radical:

REPLACEMENT SHEET

The subject of the invention is particularly, as plant growth regulators, the compounds of formula (I) whose names follow:

- N- [(4-hydroxy 3-methoxy phenoxy) acetyl] 1,4-diamino butane

- N - [(2-methyl 6-indolyloxy) acetyl] 1,4-diamino butane

- N - [(3-trifluoromethyl phenoxy) acetyl] 1,4-diamino butane - N- [(3-trifluoromethyl phenoxy) acetyl] N '- [l- (3-indolyl) acetyl] 1,4-diamino butane

- N - [(2,4-dichloro phenoxy) acetyl] 1,4-diamino butane

The products of formula (I) promote cell multiplication and differentiation. They find their use in the in vitro regeneration of new varieties of cultivated plants, such as tobacco, vines, soybeans, rubber trees, palm trees, grasses such as wheat, corn, rice or dicots such as peas, broad beans, beans or lentils. The subject of the invention is also, phytosanitary compositions containing as active principle at least one plant growth regulator defined above and very particularly phytosanitary compositions containing as plant growth regulator, the products of preparations 4, 5, 9 , 11, 24 and 27 as well as their addition salts with organic and mineral acids.

The compositions according to the invention can be in the form of powder, granules, suspensions, emulsions.

REPLACEMENT SHEET solutions containing the active principle, for example in admixture with a vehicle and / or an anionic, cationic or nonionic surfactant ensuring, inter alia, a uniform dispersion of the substances of the composition. The vehicle used can be a liquid, such as water, or alcohols.

They may, for example, be gelled compositions based on agarose.

The following preparations relate to products described and claimed in European patent application n ^β 89403614.4 filed on December 22, 1989.

PREPARATION l: N - [(6-sec-butyl 2,4-dichloro phenoxy) acetyl] 1,4-diamino butane

Stage A: N- (tert-butoxycarbonyl) N '- [(6-sec-butyl 2,4-dichloro phenoxy) acetyl] 1,4-diamino butane. To a mixture of 3.95 g of N- (tert-butoxycarbonyl) 1,4-diamino butane (preparation 1), 40 cm of chloroform and 3 cm ³ of triethylamine, a suspension of 6 is added to +10 ^β C, 2 g of (6-sec-butyl 2,4-dichloro phenoxy) acetic acid chloride obtained in stage D of the preparation below and 50 cm ³ of chloroform. The mixture is stirred for 1 hour at room temperature and then evaporated to dryness under reduced pressure.

The residue is taken up with tetrahydrofuran, filters the insoluble material, brings the filtrate to dryness under reduced pressure. The residue is chromatographed (10.15 g) on silica (eluent: hexane-ethyl acetate (7-3)), 8.42 g of expected product are obtained. F - 50 * C.

Stage B: N - [(6-sec-butyl 2,4-dichloro phenoxy) acetyl] 1,4- diamino butane, a) Obtaining the hydrochloride: The mixture is stirred at reflux for 1 hour 30 minutes 8.12 g of the product obtained in stage A, 80 cm ³ of ethanol and 20.1 cm ³ of hydrochloric ethanol -≈ '2N. It is concentrated under reduced pressure, the residue is washed with methylene chloride. 6.7 g of the expected hydrochloride are obtained. b) Obtaining the base:

6.7 g of hydrochloride are stirred with 100 cm ³ of ethanol and 3.2 g of sodium bicarbonate for 4 hours at reflux. It is filtered hot and the filtrate is concentrated under reduced pressure.

REPLACEMENT SHEET The residue is chromatographed (6.05 g) on silica (eluent: methanol-ammonia (98-2)), 4.74 g of the desired product is obtained.

Analysis for C ₁₆ H ₂₄ C1 ₂ N ₂ 0 ₂ : Calculated: C% 55.34 C% 6.96 Cl% 20.42 N% 8.07 Found: 55.2 7.1 19.5 7.8 Preparation chloride of (6-sec-butyl 2,4-dichloro phenoxy) acetic acid used at the start of preparation 1. Step A: 6-sec-butyl 2,4-dichloro phenol. 62.76 g of 6-sec-butyl phenol and 75 cm ³ of sulfuryl chloride are stirred for 1 hour 30 minutes under reflux. It is brought back to room temperature and poured onto 400 cm of water, extracted with methylene chloride and evaporated to dryness under reduced pressure. The oil obtained (89.8 g) is distilled twice Eb 82'C under 0.01 mm of mercury, 27.8 g of expected product is obtained. Step B: 6-sec-butyl 2,4-dichloro phenoxy ethyl acetate.

2.8 cm ³ of ethyl brooacetate are added at room temperature to a mixture of 5 g of the product obtained in step A and 20 cm of dimethyl sulfoxide. To the solution obtained, 4.45 g of potassium carbonate are added in portions, then the mixture is heated for 3 hours at 70/80 ° C. Poured onto a mixture of water and ice, extracted with methylene chloride and evaporated to dryness under vacuum. The residue is chromatographed (7.13 g) on silica (eluent: hexane-ethyl acetate (97-3)). 6.58 g of expected product are obtained. Step C: 6-sec-butyl 2,4-dichloro phenoxy acetic acid.

Stirred for 1 hour at 20 ° C., 6.5 g of the product obtained in step B, 15 cm ³ of ethanol and 10.65 cm ³ of 2N sodium hydroxide. Then added 10.65 cm of 2N hydrochloric acid and evaporated to dryness under reduced pressure, the residue (10 g) is taken up in 200 cm of water. It is filtered, dried and 5.83 g of expected product is obtained. Step D: Chloride of 6-sec-butyl 2,4-dichloro phenoxy acetic acid.

5.8 g of the product are stirred at reflux for two hours

3 obtained in step C with 40 cm of thionyl chloride. It is evaporated to dryness under reduced pressure, the oil obtained is washed with

REPLACEMENT SHEET benzene and evaporated to dryness under reduced pressure.

6.2 g of expected product are obtained, used as it is for obtaining the product of preparation 1. PREPARATION 2: N- [1- (3-indolyl) acetyl] 1,4-diamino butane Stage A: N- ( tert-butoxycarbonyl) N '- [1- (3-indolyl) acetyl] 1,4-diamino butane.

The procedure is carried out as in stage A of preparation 1 from 8.10 g of N- (tert-butoxycarbonyl) 1,4-diamino butane and 8.39 g of 1,3-indol acetyl chloride (obtained according to the preparation described below), in methylene chloride. The dry extract is taken up in tetrahydrofuran, the insolu¬ ble is filtered, evaporated to dryness and 16.53 g of product is obtained which is chromatographed on silica (eluent: chloroform methanol (98-2) then again in eluting acetate ^{"ethyl-hexane} (7-3) and finally ethyl acetate). 11.47 g of expected product are obtained. Analysis for ^c ιg ^H ₂₇ ^N ₃ ° ₃ ^: Calculated: C% 66.06 H% 7.88 N% 12.16 Found: 65.8 8.0 11.9 Stage B: N- [l- (3- indolyl) acetyl] 1,4-diamino butane.

The procedure is carried out as in stage B of preparation 1 using 9.35 g of the product obtained in stage A and 35 cm ³ of 1.6 N hydrochloric ethanol. After 2.28 g of double chromatography, expected product. Analysis for ^c _i 4H ₁₉ N ₃ 0 (at 1.7% water): Calculated: C% 68.54 H% 7.81 N% 17.13 Found: 68.2 7.9 16.6

Preparation of 1,3-indolacétyle chloride, used at the start of Preparation 2. To a stirred suspension at 0 C ^e 27 g of phosphorus pentachloride and 500 ml of ethyl ether was slowly added 20 g of indole acid acetic, the mixture is stirred for another 15 minutes at 0 ^β C. It is then concentrated under reduced pressure to a

3. _t total volume of 200 cm then add 2 liters of hexane, stir for 2 hours, wring and dry under reduced pressure. 8.38 g of expected product are obtained. F = 66 ^β C. PREPARATION 3: N- (7-coumarinyloxyacetyl) 1,4- diamino butane hydrochloride

REPLACEMENT SHEET Stage A: N- (tert-butoxycarbonyl) N '- (7-coumarinyloxyacetyl)

1,4-diamino butane.

To a solution of 10 g of 7-hydroxy coumarin in

100 cm of diethyl formamide, 2.96 g of 50% sodium hydride in oil are added at room temperature. Stir for 45 minutes at room temperature and add

17.98 g of chloracetyl N- (tert-butoxycarbonyl) 1,4-diamino butane (preparation below) dissolved in 60 cm ³ of dimethyl formamide, the mixture is stirred for 5 hours at 90 ° C. and then 60 hours at room temperature. It is evaporated under reduced pressure, the residue is taken up (37.6 g) in 180 cm of water, drained, paste with isopropyl ether to obtain 23.25 g of the desired product.

F = 120 ^β C.

Stage B: N- (7-coumarinyloxyacetyl) 1,4-diamino butane hydrochloride.

19.85 g of product obtained in stage A and 38.1 cm ³ of a solution of 2N hydrochloric ethanol in 200 cm ³ of ethanol are stirred for 1 hour at reflux. Evaporated to dryness, 18.67 g of crude product are obtained. F = 90 "C. Recrystallized from 20 ml of acetonitrile-water mixture

(95-5) at reflux, wring out, paste with isopropyl ether. 8.44 g of expected product are obtained. F ≈ 160 ° C.

Analysis for ^c i5 ^H ιg ^clN 2 ° 4 ( ^at ' ⁸ * of water): Calculated: C% 55.13 H% 5.86 Cl% 10.85 N% 8.57 Found: 52.3 6.2 10.6 8.2

Preparation of chloracetyl N- (tert-butoxycarbonyl) 1,4-diamino butane used for preparation 3.

To a stirred mixture at 0 ^β C of 9.4 g of N- (tert-butoxycar-

3 bonyl) 1,4-diamino butane and 7.3 cm of triethylamine in 100 cm ³ of tetrahydrofuran, a solution of 5.65 g of chloracetic acid chloride in 50 cm of tetrahydrofuran is added at 0 ^β C. The mixture is stirred for 2 hours at room temperature. Evaporated to dryness and the residue is taken up with 100 cm of chloride

3 methylene and 50 cm of water, the organic fraction is decanted and concentrated to dryness, under reduced pressure, 12 g of the expected product are obtained. F = 98-100 * C.

PREPARATION 4: N- (3-trifluoromethyl phenoxy acetyl) 1,4-diamino butane hydrochloride

REPLACEMENT SHEET Stage A: N- (tert-butoxycarbonyl) N '- (3-trifluoromethyl phenoxy acetyl) 1,4-diamino butane.

6.44 g of trifluoro acid chloride are added to a solution, cooled to + 10 ° C., of 10.2 g of N- (tert-butoxycarbonyl) 1,4-diamino butane in 150 cm ³ of chloroform chloroform - ethyl phenoxy acetic (preparation below) in solution

₃ in 60 cm of chloroform. The mixture is stirred for two hours at room temperature. It is concentrated under reduced pressure, taken up in water, drained and 9.85 g of sought product is obtained. F = 86 ^β C. Stage B: N- (3-trifluoromethyl phenoxy acetyl) 1,4-diamino butane hydrochloride.

Stirred for 1 hour at reflux, 9.8 g of N- (tert-butoxycarbonyl) N '- (3-trifluoromethyl phenoxy acetyl) 1,4-diamino butane obtained in stage A, 90 cm ³ of ethanol and 28 cm ³ of 2N hydrochloric ethanol. It is concentrated to dryness under reduced pressure, 11.9 g of product are obtained which is crystallized from ethyl acetate, 7.55 g of the expected product are collected. F = 90 * C. Analysis for C ₁₃ H ₁₈ C1F ₃ N ₂ 0 ₂ (hydrated with 2.56% water): Calculated: C% 47.79 H% 5.55. F% 10.85 Cl% 17.44 N% 8.57 Found: 47.0 5.7 10.5 17.0 8.1 Preparation of 3-trifluoromethyl phenoxy acetic acid chloride, used from the preparation 4. Step A: 3-trifluoromethyl phenoxy ethyl acetate.

3 ₃ To a mixture of 15 cm of 3-tπfluorométacresol and 60 c of dimethylsulfoxide, 15 cm of ethyl bromoacetate are added and then in portions 24 g of potassium carbonate. It is heated for five hours at 70-80 ^β C, then poured over 400 cm of a mixture of water and ice. Extracted with methylene chloride, evaporated to dryness under reduced pressure, the residue is taken up in dilute sodium hydroxide, extracted with methylene chloride and concentrated to dryness under reduced pressure, 28.61 g of expected product is obtained used as is for the next step. Step B: 3-trifluoromethyl phenoxy acetic acid.

A solution of 23.3 g of prop is stirred for 1 hour

3 ₃ duit obtained in step A in 50 cm of ethanol and 47 cm of

3 soda 2N. 47 cm 2N hydrochloric acid are then added.

REPLACEMENT SHEET It is concentrated to dryness under reduced pressure, the residue is taken up in water and drained. 19.73 g of expected product are obtained. F = 96 ^β C.

Step C: Chloride of 3-trifluoromethyl phenoxy acetic acid.

Stirred for 1 hour at reflux, a solution of 6 g of 3-trifluoromethyl phenoxy acetic acid (obtained in step

B) in 36 cm of thionyl chloride, evaporated to dryness under reduced pressure, 6.44 g of sought product is obtained, used as it is at the start of preparation 4.

PREPARATION 5: N- (3-trifluoromethyl phenoxy acetyl) N ^" - [1- (3- indol acetyl)] 1,4-diamino butane

6.44 g of 2-chloro N-methyl pyridinium iodide and

₃

100 cm of tetrahydrofuran, 3.72 g of 3-indol acetic acid are added and then slowly a solution of 6 g of 3-trifluoromethyl phenoxy acetyl 1,4-diamino butane (obtained in stage B of preparation 4) in 150 cm of tetrahydrofuran, then add 7 c of triethylamine and stir for 6 hours at reflux and 16 hours at room temperature. Evaporated to dryness under reduced pressure and the residue (16.7 g) is chromatographed on silica (eluent: methylene chloride-tetrahydrofuran (1-1)), 6.19 g of expected product is obtained. Analysis for C ₂₃ H ₂₄ F ₃ N ₃ 0 ₃ : Calculated: C% 61.74 H% 5.41 F% 12.74 N% 9.39 Found: 61.4 5.5 12.1 9.4

PREPARATION 6: Dichlorohydrate of 3.3 • - [N- (6-sec-butyl 2,4- dichloro phenoxy) acetyl] 3,3'-âiaminodipropylamine Stage A: N- [(6-sec-butyl 2,4- dichlorophenoxy) acetyl] thiazolidine-2-thione. To a solution of 9.78 g of (6-sec-butyl 2,4-dichloro phenoxy) acetic acid (prepared as in step C of the preparation used in preparation 1), 4.63 g of 2- mercaptothiazolme in 80 cm of methylene chloride, a solution of 8.09 g of dicyclohexylcarbodiimide, 340 mg of dimethylamino pyridine in 60 cm ³ of methylene chloride is added at -5/0 ^β C. Stirred 10 minutes at 0 ^β C and four hours at room temperature. The insoluble material is filtered, brought to dryness and the residue is chromatographed on silica (eluent: hexane-acetate of ethyl (7-3)), 10.3 g of expected product are obtained. F = 96 ^β C.

Stage B: 3.3 '- [N - [(6-sec-butyl 2,4-dichloro phenoxy) acetyl] N "- (tert-butoxycarbonyl)] 3,3'-diaminodipropylamine. To a solution of 1.59 g of product obtained according to Preparation and Company .on ci. below, in 15 cm3 of methylene chloride is added at 0 ^° C a solution of 2.6 g of the product of

3 stage A in 25 cm of methylene chloride. We shake

45 minutes at room temperature, bring to dryness and chromatography on silica (eluent: methanol), 3.19 g of expected product is obtained.

Stage C: 3,3 '- [N- (6-sec-butyl 2,4-dichloro phenoxy) acetyl] 3,3'-diaminodipropylamine dihydrochloride.

To a solution of 3.19 g of product obtained in stage B in 30 cm of ethanol, 6.4 cm ³ of a 2.25 N solution of hydrochloric ethanol are added, the mixture is heated for 1 hour at reflux, brought to dry under reduced pressure and pastes the residue in isopropyl ether. 2.58 g of expected product is obtained. F = 196 ^β C. Analysis for C ₁₈ H ₃ -0 ₂ N ₃ C1 ₄ , hydrated product at 2%: Calculated: C% 46.67 H% 6.74 Cl% 30.61 N% 9.07 Found: 46.0 6.9 29.9 9.0 Preparation of N- (tert-butoxycarbonyl) (3-amino propyl) 1,3-propanediamine, used in stage B of preparation 6. To a solution of 39.3 g of 3.3 * -diaminodipropylamine in 300 cm ³ of methylene chloride, a solution of 33 g of tert-butyl dicarbonate in 200 cm of methylene chloride is added at 5 ° C. Agitation is carried out for 16 hours at 20 ° C., water is added and then decanted, evaporated to dryness and chromatography on silica (eluent: methanol-ammonia (98-2)), 15.5 g of expected product are obtained, used as which at the start of the preparation 6.

PREPARATION 7: N - [(6-sec-butyl 2,4-dichlorophenoxy) acetyl] 4-guanidine aminobutane trifluoroacetate Stage A: N- [(6-sec-butyl 2,4-dichlorophenoxy) acetyl] 4- (di-tert-butoxycarbonyl guanidine) aminobutane.

To a solution of 4.89 g of N- (di-tert-butoxycarbonyl guanidine) aminobutane (prepared as below) in 50 cm ³

REPLACEMENT SHEET of methylene chloride, 3.43 g of product are added to O'C

„3 obtained in stage A of preparation 6, dissolved in 40 c of methylene chloride, stirred for 1 hour at ambient temperature then brought to dryness and the residue is chromatographed on silica (eluent: hexane-acetate ethyl (7-3) at 1% triethylamine). 3.63 g of expected product is obtained. Stage B: N - [(6-sec-butyl 2,4-dichloro phenoxy) acetyl] 4-guanidine aminobutane trifluoroacetate.

2.4 cm of trifluoro acetic acid are added at ambient temperature to a solution of 1.82 g of product obtained in stage A in methylene chloride. Stirred for 48 hours and brought to dryness under reduced pressure, 1.56 g of expected product is obtained. Analysis for C ₁₇ H ₃₁ N ₄ 0 ₂ C1 ₂ , 1.25 M CF ₃ C0 ₂ H solvated with 1.25 mol of trifluoroacetic acid.

Calculated: C% 45.34 H% 5.4 N% 11.13 Cl% 14.09 F% 11.32 Found: 44.03 5.16 10.53 13.33 13.4 Preparation of N ₁ - ( N ' ₁ , N' ₂ -bis-tert-butoxycarbonyl formamidino) 1,4-diamino butane, used at the start of preparation 7.

Step A: N-benzyloxy carbonyl 1,4-diamino butane.

_{É 3}

To a mixture of 23 g of 1,4-dιammo butane, 50 c of water, a solution of 46 g of acid is added, without exceeding 30 ^β C

3 sulfonic methane in 50 cm of water. The reaction medium is diluted with 140 cm of ethanol. A solution of 39 g of benzyl chloroformate is added alternately at pH 3.5-5.0

3 in 50 cm of 1,2-dιmethoxy ethane and 100 cm of a 50% aqueous solution of potassium acetate. The additions are made alternately so as to maintain the pH value between 3.5 and 5.0. Stirred for another 1 hour 30 at 20-25 ^β C and evaporated under reduced pressure. The residue is poured into 500 cm of water, the insoluble material is filtered, the filtrate is washed with 3 times

3. 3

150 cm of benzene and then 100 cm of 30% sodium hydroxide saturated with sodium chloride are added. Extraction is carried out with benzene, evaporated to dryness under reduced pressure, 19.10 g of expected product are obtained. Step B: N, N'-bis- (tert-butoxycarbonyl) methyl thioisourée.

Stirred for 48 hours at 20 ^° C, 58.1 g of ditertbutyle

REPLACEMENT dicarbonate, 25.3 g of methyl thioisouree sulfate, 50 g of

3 sodium bicarbonate, 500 cm of water and 500 cm of methylene chloride. Decanted, extracted with methylene chloride evaporated to dryness. 27 g of expected product are obtained. F = 118'C.

Stage C: N ₁ - (N ' ₁ , N' ₂ -bis-tert-butoxycarbonyl formamidino) N ₂ - carbobenzyloxy 1,4-diamino butane.

A mixture of 13.4 g of product obtained in step A, 14.5 g of N, N'-bis- (tert-buto-xycarbonyl) methyl thioisouree obtained in step B is stirred for 2 hours at reflux. and 100 cm ³ of tetrahydrofuran. It is concentrated under reduced pressure. The residue is taken up in 200 cm of chloroform, washed with 30 cm of a saturated solution of sodium bicarbonate in water and concentrated to dryness under reduced pressure. Chromatography on silica (eluent: ethyl acetate). 12.7 g of expected product are obtained.

Step D: N ₁ - (N ' ₁ , N' ₂ -bis-tert-butoxycarbonyl formamidino) 1,4-diamino butane.

To a solution of 12.7 g of product obtained in Stage C in 100 cm ³ of ethanol, 1 g of activated carbon containing 10% palladium is added and the mixture is stirred under hydrogen pressure until absorption is complete. The catalyst is filtered and the fil¬ trate is brought to dryness under reduced pressure. 6.6 g of expected product are obtained. NMR (CDC1 ₃ )

2.74 (m) 2H 3.43 (m) 2H

^{1.5 (S)} COOtBu

1.51 (s) 1.5 to 1.8 (m) CH ₂ central

11.5 mobile proton

PREPARATION 8: N - [(6-sec-butyl 2,4-dichloro phenoxy) acetyl] NN ¹ -spermidine dihydrochloride Stage A: N - [(6-sec-butyl 2,4-dichloro phenoxy) acetyl] NN ¹ - (tert-butoxycarbonyl) spermidine.

The operation is carried out as in stage B of preparation 6 using 1.62 g of NN • -tert-butoxycarbonyl spermidine (preparation

REPLACEMENT SHEET below) and 2.5 g of N - [(6-sec-butyl 2,4-dichloro phenoxy) acetyl] thiazolidine-2-thione, prepared in stage A of preparation 6. 2.64 is obtained g of expected product. Stage B: N-hydrochloride - [(6-sec-butyl 2,4-dichlorophenoxy) 5 acetyl] NN'-spermidine.

The procedure is carried out as in stage C of Example 6. 2.23 g of expected product are obtained.

Analysis for C _ιg H ₃₃ 0 ₂ N ₃ Cl ₄ , 2% hydrated product: Calculated: C% 47.8 H% 6.97 N% 8.8 Cl% 29.71 10 Found: 46.7 7.2 8.7 28.7

Preparation of N- (tert-butoxycarbonyl) spermidine, used in stage A of Example 8.

Step A: N-phthaloyl aminobutyraldehyde diethylacetal.

To a solution of 30.1 g of N-carbethoxy phthalide in

3,

15,150 cm of tetrahydrofuran, a solution of 24.8 g of 4-aminobutyraldehyde diethylacetal in 250 cm ³ of tetrahydrofuran is added at 20 ^β C. The mixture is stirred for 3 hours at reflux. The solvent is evaporated off and the residue is chromatographed on silica (eluent: hexane-ethyl acetate (65-35)), 34.9 g are obtained

20 of sought product.

Analysis for ^c i5 ^H 2 _i ^N0 4 ^:

Calculated: C% 65.97 H% 7.26 N% 4.80 Found: 66.0 7.2 4.7 Stage B: 4-phthalimido butanal. 25.9 g of product obtained are stirred for 3 hours.

₃ step A in 350 cm 2N hydrochloric acid, diluted with water and extracted with methylene chloride. Evaporated to dryness and 24 g of expected product are obtained. F = 70 "C. Analysis for ^c i2 ^H n ^N0 3 ^:

30 Calculated: C% 66.35 H% 5.1 N% 6.45 Found: 66.2 4.9 6.3

Step C: N '- (phthaloyl) N "- (tert-butoxycarbonyl) spermidine. To a solution of 8.68 g of product obtained in step B, 7 g of N- (tert-butoxycarbonyl) 1,3- diamino propane in

35 120 cm of ethanol, 2.4 g of palladium on carbon are added and the mixture is stirred under a hydrogen atmosphere until absorption is complete. The catalyst is filtered, the filtrate is evaporated to dryness and chromatography on silica (eluent: methanol at 1% ammonia). We

REPLACEMENT SHEET 8.5 g of expected product is obtained.

Analysis for ^C 20 ^H 29 ^N 3 ° 4 ^: Calculated: C% 63.98 H% 7.78 N% 11.19 Found: 63.1 8.2 10.4 Step D: N- (tert-butoxycarbonyl) spermidine .

To a solution of 8.5 g of product obtained in step C in 250 cm of ethanol, 4.5 cm ³ of 80% hydrazine hydrate is added. The mixture is heated for 1 hour at reflux, the insoluble material is filtered and evaporated to dryness under reduced pressure. The residue is taken up in methylene chloride, washed with water and evaporated to dryness under vacuum. 4.13 g of expected product are obtained. NMR (CDC1 ₃ )

2.45 - 2.92, N-CH 1.42 - 1.83 CH ₂ central

3.05 - 3.36 ² 1.28 NH ₂ 1.45 (S9H) OtBu 5.16 NH

PREPARATION 9: N- (2,4-dichloro phenoxy acé¬ tyl) 1,4-diamino butane hydrochloride

Stage A: N- (tert-butoxycarbonyl) N '- (2,4-dichloro phenoxy acetyl) 1,4-diamino butane. To a mixture of 8.6 g of U- (tert-butoxycarbonyl) 1,4-diamino butane, 120 cm ³ of methylene chloride, and 7 cm ³ of triethylamine is added, without exceeding 25 ^β C, 11 g of 2,4-dichloro phenoxy acetic acid chloride dissolved in 40 cm of methylene chloride. The mixture is stirred for 30 minutes and then concentrated to dryness under reduced pressure. The residue is taken up in 200 cm of tetrahydrofuran, the insoluble material is filtered and the filtrate is brought to dryness under reduced pressure. 18.53 g of crude product are collected (F ≈ 101 'C) which are recrystallized from 740 cm ³ of isopropyl ether. 17.43 g of expected product are obtained (F = 110 ^β C). 5.39 g are chromatographed on silica (eluent: hexane-ethyl acetate (6-4)), 4.48 g of sought product is collected. F = 114 ^β C.

Analysis for ^c τ7 ^H 24 ^C 2 ^N 2 ° 4 ^:

Calculated: C% 52.18 H% 6.18 Cl% 18.12 N% 7.16 Found: 52.1 6.2 18.3 7.0

Stage B: N- (2,4-dichloro phenoxy acetyl) 1,4-diamino butane hydrochloride.

10.15 g of product are stirred at reflux for 2 hours.

REPLACEMENT SHEET 3 3 obtained as in stage A, 120 c of ethanol and 35 cm of a 1.5 N solution of hydrochloric ethanol. It is concentrated under reduced pressure, the crude product obtained, 12.56 g (F = 90 ^β C), is recrystallized in 15 volumes of an ethanol-ethyl acetate mixture (1-1), 5.88 g is obtained. of expected product. F = 140 ^β C.

Analysis for C ₁₂ H ₁₇ C1 ₃ N ₂ 0 ₂ :

Calculated: C% 43.98 H% 5.22 Cl% 32.46 N% 8.55 Found: 43.9 5.3 32.2 8.5 Preparation of 2,4-dichlorophenoxyacetyl chloride used in stage A of preparation 9.

To a solution of 130 g of 2,4-dichlorophenoxy acid

. 3 acetic acid in 150 cm of benzene, 46 ml are added in 30 minutes

₃ cm of thionyl chloride, the mixture is then heated at reflux for 1 hour then the solvent and the excess of thionyl chloride are removed under reduced pressure and distilled under 0.1 mm of mercury. 91.4 g of sought product is obtained.

Eb = 120 ° under 0.1 mm of mercury.

PREPARATION 10: 1- (2, -dichloro phenoxy acetyl) triaza 1,6,10-decane dihydrochloride

Stage A: 1-tert-butoxycarbonyl 10- (2,4-dichloro. Phenoxy acetyl) triaza 1,6,10-decane.

To a mixture of 5.82 g of product obtained in stage B of Example 9 with 2.76 g of potassium carbonate and 30 cm of terbutanol brought to reflux, a solution of 4.5 g of

3- [(tert-butoxycarbonyl) amino] 1-bromopropane in 18 cm ³ of terbutanol. After 5 hours of reflux, the mixture is cooled, the insoluble material is filtered and the filtrate is evaporated to dryness. The residue is chromatographed (11.6 g) on silica (eluent: methanol). 3.44 g of expected product are obtained.

Stage B: 1- (2,4-dichlorophenoxy acetyl) triaza 1,6,10-decane dihydrochloride.

A mixture of 3.44 g is stirred at reflux for 4 hours.

3 of product obtained in stage A, 100 cm of ethanol and 13 ml of an approximately 2N solution of hydrochloric ethanol. Cool and drain, 2.4 g of the expected product are obtained. F = 220'C. Analysis for C, ₅ H ₂₃ C1 ₂ N ₃ 0 ₂ , Hcl:

REPLACEMENT SHEET Calculated: C% 42.77 H% 5.98 N% 9.98 Cl% 33.67 Found: 42.8 6.0 9.9 33.2 PREPARATION 11: 1.10-bis- (2.4- dichlorophenoxy acetyl) 6-methyl triaza 1,6,10-decane To a mixture of 1.6 g of 6-methyl triaza 1,6,10-decane (preparation below), 20 cm ³ of chloroform and 2.02 g of triethylamine, 4.8 g of 2,4-dichlorophenoxy acetic acid chloride (preparation 9), dissolved in 15 cm ³ of chloroform, are added, without exceeding 30 ° C. After 3 hours of stirring at 20 ^β C, evaporated to dryness under reduced pressure and the residue is taken up with 180 cm of tetrahydrofuran, filter the insoluble material and evaporate the filtrate, to dryness under reduced pressure the residue is chromatographed (6, 8 g) on silica (eluent: chloroform-methanol (9-1)). 4 g of expected product are obtained.

Analysis for C ₂₄ H _2Q C1 ₄ N ₃ 0 ₄ :

Calculated: C% 50.98 H% 5.17 Cl% 25.09 N% 7.43

Found: 50.5 5.0 24.9 7.4

Preparation of 6-methyl triaza 1,6,10-decane used at the start of preparation 11.

Stage A: 3-methyl 3-aza 1,6-dicyano hexane.

To a stirred mixture at 20 ° C. of 42 g of methyl amino propionitrile, 325 cm of terbutyl alcohol and 70 g of potassium carbonate, 75 g of 4-bromo-butyronitrile are added, the mixture is stirred for 2 hours at reflux then 16 hours at room temperature. The insoluble material is filtered, the filtrate is concentrated and the residue is chromatographed (96 g) on silica (eluent: chloroform-acetone-cyclohexane (1-1-1)). 54 g of expected product are obtained. NMR (CDC1 ₃ )

95 to 120.5 Hz CH ₂ central

137 HZ ^N ~ ^CH ₃ 137 at 182 Hz the other CH ₂ . Stage B: 6-methyl triaza 1,6,10-decane. 10 g of product obtained in Stage A, 20 cm ³ of ethanol and 2 g of raney nickel are added to a solution of 3 g of sodium hydroxide tablet in 55 cm ³ of ethanol 95. The mixture is stirred under a hydrogen atmosphere until complete absorption is complete. We

REPLACEMENT SHEET filters the catalyst and concentrates the filtrate at low volume, adds 60 cm of water. It is released with sodium hydroxide solution, the oil thus separated is collected and the aqueous phase is extracted with chloroform. The extracts combined with the oil are concentrated to dryness. 11 g of expected product are obtained. NMR (CDC1 ₃ )

70 to 110 Hz central CH ₂ 6H 132 Hz N-CH ₃ 132 to 180 Hz CH ₂ ~ N 8H

10 73 Hz NH ₂ .

PREPARATION 12: N- (1-naphthyl acetyl) 1,4-diamino butane and its hydrochloride;

Stage A: N- (tert-butoxycarbonyl) N '- (1-naphthyl acetyl) 1,4-diamino butane.

15 To a solution cooled to +10 ^C C of 15 g of N- (tert-buto¬ xycarbonyl) 1,4-diamino butane, 100 cm of chloroform and 14 cm ³ of triethylamine, a solution is added to +10 "C 16.3 g of 1-naphthyl acetic acid chloride in 80 cm of chloroform. After 1 hour of stirring at room temperature,

20 concentrated to dryness under reduced pressure. The residue is taken up in water, drained and dried under reduced pressure at 50 ° C. 27.8 g of expected product are obtained.

Stage B: N- (1-naphthyl acetyl) 1,4-diamino butane (and its hydrochloride).

A) Preparation of the hydrochloride:

To a mixture of 27.76 g of the product obtained in stage A and

3. 3

200 cm of ethanol, 86 cm of ethanol-hydrochloric acid -2N are added and the mixture is stirred for 1 hour at reflux. Concentration to dryness under reduced pressure. 23.4 g of intermediate hydrochloride F - 130 "C are obtained, isolated from ethyl acetate. B) Obtaining the amine:

The 23.4 g of intermediate hydrochloride is taken up with. 3

200 cm of water, we have 80 cm of sodium hydroxide and stirred for 10 minutes at room temperature. Extracted with methylene chloride 35, dried, filtered and evaporated to dryness under reduced pressure, 19.08 g of crude product are obtained (F <50 ^β C) which are chromatographed on silica (eluent: methanol-ammonia ( 98-2)). The product obtained is pasted in ethyl acetate

REPLACEMENT SHEET then in ether. 15.87 g of expected product are obtained.

F = 96 * C.

Analysis for C ₁₆ H ₂₀ N ₂ O (0.8% hydrated):

Calculated: C% 74.97 H% 7.86 N% 10.93 Found: 74.0 7.9 10.7

Preparation of 1-naphthyl acetic acid chloride used at the start of preparation 12.

The mixture is heated with stirring for 2 hours at reflux,

15 g of 1-naphthyl acetic acid and 90 cm ³ of thionyl chloride. The solution is concentrated under reduced pressure and the residue is taken up in toluene and concentrated to dryness under reduced pressure. 16.3 g of expected product are obtained, used as it is at the start of preparation 12.

PREPARATION 13: Dichlorhydrate l- (l-naphthyl acetyl) triaza 1,6,10-decane

Stage A: 1- (1- naphthyl acetyl) 10- (tert-butoxycarbonyl) triaza

1,6,10-decane.

To a solution of 8.8 g of product obtained in stage B of

. 3 preparation 12 in 50 c of terbutanol and 4.7 g of potassium carbonate, 8.1 g of 3 - [(tert-butoxycarbonyl) a ino] 1-bromopropane dissolved in 40 are added at reflux cm ³ of terbutanol. The mixture is stirred for 3 hours 30 minutes at reflux and 16 hours at room temperature. The insoluble material is filtered, concentrated under reduced pressure. The residue is chromatographed (17.21 g) on silica (eluent: methanol). 6.16 g of expected product are collected.

Stage B: 1- (1-naphthyl acetyl) triaza dihydrochloride 1,6,10-decane.

Agitation is carried out for 2 hours 30 minutes at reflux, 5.9 g of product obtained

3 ₃ in stage A, 60 cm of ethanol and 26 cm of 2N hydrochloric ethanol. It is filtered, paste with ethyl acetate and then isopropyl ether. 4.78 g of expected product are obtained. F = 218'C. Analysis for C _ιg H _2g Cl ₂ N ₃ 0: Calculated: C% 59.06 H% 7.57 Cl% 18.35 N% 10.88 Found: 58.8 7.6 18.3 10.7 PREPARATION 14 : N- (naphthoxy acetyl) 1,4- diamino butane hydrochloride

SHEET Stage A: N '- (tert-butoxycarbonyl) N- (2-naphthyl acetyl) 1,4-diamino butane.

To a solution of 10.32 g of N- (tert-butoxycarbonyl) 1,4-

3 diammothbutane in 110 cm of tetrahydrofuran and 6.7 g of triethylamine, 11.16 g of naphthoxy acetic acid chloride in solution in 50 cm of tetrahydrofuran are added, between 0 ° and +10 ^β C. The mixture is stirred for 1 hour 30 minutes at ambient temperature.

The insoluble material is filtered, evaporated to dryness and the residue is chromatographed (17.78 g) on silica (eluent: hexane-ethyl acetate (1-1)). 10 g of expected product are obtained. F = 102 ^β C.

Stage B: N- (naphthoxy acetyl) 1,4-diamino butane hydrochloride.

7.66 g of the product obtained in Stage A, 80 cm of ethanol and 14.7 cm ³ of -2N hydrochloric ethanol are stirred at reflux for 1 hour 30 minutes. It is slowly cooled, wrung and dried. 4.56 g of expected product is obtained. F = 208 "C.

Analysis for ^c i ₆ ^H ₂₀ ^N 2 ° 2 ' ^Hcl:

Calculated: C% 62.23 H% 6.85 N% 9.07 Cl% 11.48

Found: 62.2 6.9 9.0 11.3 Preparation of naphthoxy acetic acid chloride, used at the start of preparation 14.

Is brought to reflux for 2 hours, 10 g of naphth¬ oxy acetic acid and 60 cm ³ of thionyl chloride, evaporated to dryness under reduced pressure and proceeds to several entrainments with benzene. 11.16 g of expected product are obtained, used as is at the start of preparation 14. PREPARATION 15: 1- (2-naphthoxy acetyl) triaza dihydrochloride 1,6,10-decane Stage A: 1- (2 -naphthoxy acetyl) 10- (tert-butoxycarbonyl) triaza 1,6,10-decane.

To a mixture stirred at reflux of 5 g of N- (2-naphthoxy acetyl) 1,4-diamino butane (preparation below) 20 cm ³ of terbutanol and 2.54 g of potassium carbonate, 4.37 is added g of 3- [(tert-butoxycarbonyl) amino] 1-bromopropane and 20 cm ³ of terbutanol. The mixture is stirred for 3 hours 30 minutes at reflux and 16 hours at room temperature. The insoluble material is filtered, evaporated under vacuum, chromatography on silica (eluent: methanol at 0.5% ammonia), 2.9 g of expected product is obtained.

REPLACEMENT SHEET Stage B: 1- (2-naphthoxy acetyl) triaza dihydrochloride 1,6,10-decane.

2.823 g of product obtained in Stage A, 14 cm of ethanol and 8.5 cm of 2N hydrochloric ethanol are stirred for 2 hours at reflux. It is drained under argon and dried under reduced pressure. 2 g of expected product are obtained. F> 260 ^β C. Analysis for C _ιg H ₂₇ N ₃ 0 ₂ 2, HC1:

Calculated: C% 56.71 H% 7.26 N% 10.44 Cl% 17.62 Found: 56.5 7.2 10.5 17.5 Preparation of N- (2-naphthoxy acetyl) 1.4- diamino butane used at the start of preparation 15.

A mixture of 10.32 g of product obtained in preparation 14, 200 cm ³ of ethanol and 3.37 g of sodium bicarbonate is stirred for 4 hours at reflux. Evaporated to dryness and crystallized from 1 * isopropyl ether, 10 g of expected product are obtained. Mp 58 ° C.

PREPARATION 16; N-2-allyl 3-trifluoromethylphenoxyacetyl) 1,4-diamino butane and its hydrochloride. Stage A: N-ftert-butoxcarbonyl) N '- [(2-allyl 3-trifluoromethyl) phenoxyacetyl] diamino 1,4-butane.

The procedure is as in Preparation 1, using 4.99 g of N- (tert-butoxycarbonyl) 1,4-diaminobutane and 7.40 g of acetic acid chloride (2-allyl 3-trifluoromethyl) phenoxy acetic, 8.83 g of expected product is obtained. Stage B: N-2-allyl 3-trifluoromethylphenoxyacetyl) 1,4-diamino butane and its hydrochloride.

By operating as in preparation 1 from 8.7 g of product obtained in stage A and 23 cm of approximately 2N hydrochloric acid in ethanol, 8.52 g of hydrochloride were obtained which was basified with 23 cm of sodium hydroxide N. 1.37 g of expected product is obtained in the form of the base.

Analysis for ^c i6 ^H 2i ^F 3 ^N 2 ° 2 ^{solvated at} 2% H ₂ 0 Calculated: C% 58.17 H% 6.41 F% 17.25 N% 8.48 Found: 57.1 6.4 16 , 7 8.3 Preparation of 2-allyl 3-trifluoromethylphenoxy acid chloride used starting from preparation 16. Stage A; 3-trifluoromethylphenoxyallyl.

35.2 g of potassium carbonate are added to 30 cm of 3-

REPLACEMENT SHEET trifluoromethylphenol in 50 c of methyl ethyl ketone. It is heated for 1 hour at reflux, allowed to return to room temperature, added 26 cm of allyl bromide in 10 cm ³ of methyl ethyl ketone, stirred for 1 hour, heated for 1 hour and a half at reflux, allowed to return to room temperature and kept under agitation. Extracted with methylene chloride, dried and concentrated, 51.5 g of crude product is recovered which is taken up in water, made alkaline with sodium hydroxide, extracted with methylene chloride, dried and concentrated to dryness . 48.21 g of expected product are obtained.

Stage B: 2-allyl 5-trifluoromethylphenol and corresponding 3-trifluoromethyl isomer.

29.7 g of product obtained in stage A are heated under reflux for 20 hours, allowed to return to ambient temperature, chromatography on silica (eluent: n-hexane-ethyl acetate 9-1) and 8.79 g of product, rf 0.32 (isomer A 5CF ₃ ) and 12.36 g of product, rf 0.25 (isomer B 3CF ₃ ). Stage C; 2- allyl 3-trifluoromethylphenoxy ethyl acetate. 5.8 g of potassium carbonate are added to 6 g of 3-CF _{3 product} obtained in stage B in 30 c of methyl ethyl ketone and the mixture is heated for 1 hour at reflux. Allow to return to room temperature, add 3.7 cm of ethyl bromoacetate, heat for 1 hour at reflux, pour into water, extract with methylene chloride, dry and concentrate under reduced pressure. The crude product obtained is taken up in water, made alkaline with sodium hydroxide, extracted with methylene chloride, dried and the solvent evaporates. 8.17 g of expected product are collected. Stage D; 2-allyl 3-trifluoromethylphenoxy acetic acid.

8.1 g of product obtained in Stage C in 50 c of ethanol are stirred for 1 hour at room temperature in the presence of 14 cm ³ of 2N sodium hydroxide. 14 cm ³ of 2N hydrochloric acid are then added, the mixture is stirred for 15 minutes and concentrated. 10.19 g of crude product are obtained which is taken up in water. Extraction is carried out with methylene chloride, the solvent is dried and evaporated to obtain 7.26 g of the expected product.

Stage E: 2-Allyl 3-trifluoromethylphenoxy acetic acid chloride.

7 g of product obtained at reflux are heated for 2 hours.

REPLACEMENT SHEET stage D in 50 cm3 of thionyl chloride. It is concentrated, the residue is taken up in toluene, and the solvents are removed under reduced pressure. The crude product used is obtained as is, starting from preparation 16. PREPARATION 17: N- (2-allyl 5-trifluoromethylphenoxyacetyl) diamino 1,4-butane and its hydrochloride.

Stage A: N-tert-butoxycarbonyl N ¹ - [2-allyl 5-trifluoromethylphenoxyacetyl] diamino 1,4-butane.

The procedure is as in Preparation 1, using 3.71 g of N- (tert-butoxycarbonyl) 1,4-diaminobutane and 5.5 g of (2-allyl 5-trifluoromethyl) phenoxy acetic acid chloride. 8.36 g of expected product are obtained.

Stage B: N- (2-allyl 5-trifluoromethylphenoxyacetyl) diamino

1,4-butane and its hydrochloride. The procedure is as in preparation 1 using 8.20 g of product obtained in stage A and 21.1 cm ³ of approximately 2N hydrochloric acid in ethanol and 3.56 g of hydrochloride are obtained which is made alkaline with 9 , 7 c of sodium hydroxide. After extraction with methylene chloride, concentration of the organic phase and chromatography of the residue on silica (eluent: methanol-ammonia 98-2), 2.17 g of expected product is obtained in the form of the base.

Analysis for ^c i6 ^H 21 ^F 3 ^N 2 ° 2 ^{solvated at 2% H} 2 ° Calculated: C% 58.17 H% 6.41 F% 17.25 N% 8.48 Found: 56.8 6.4 16 , 6 8.1

Preparation of 2-allyl 5-trifluoromethylphenoxy acetic acid chloride used starting from preparation 17. Stage A: 2-allyl 5-trifluoromethylphenoxy ethyl acetate. The procedure is carried out as in stage C of preparation 16 using initially 5 g of the isomer A obtained in stage B of the

3 preparation 16 and 3.1 cm of ethyl bromoacetate. We obtain

6.33 g of expected product.

Stage B: 2-allyl 5-trifluoromethylphenoxy acetic acid.

The operation is carried out as in stage D of preparation 16 starting from 6.25 g of product obtained in stage A, 10.9 cm of 2N sodium hydroxide in 40 cm ³ of ethanol and then adding 10.9 cm of 2N hydrochloric acid . 5.28 g of expected product are recovered. Stage C: 2-allyl 5-trifluoromethylphenox acid chloride

FE acetic.

By operating as in stage E of preparation 16 from 5.2 g of product obtained above, 40 cm ³ of thionyl chloride, 5.55 g of expected product is obtained, used as it is in stage A of preparation 17.

PREPARATION 18: N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl 5- (guanidine) aminopentane hydrochloride. Stage A; N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl 5- [(diterbutoxycarbonyl) guanidine) aminopentane. The procedure is carried out as in stage A of preparation 7 using at the start 6 g of 5- (diterbutoxycarbonyl guanidine) amino¬ pentane and 5.5 g of product obtained as in stage A of preparation 6. After chromatography on silica (eluent: methylene chloride), 6.52 g of expected product. Stage B: N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl 5- (guanidine) aminopentane hydrochloride.

7 cm of an ethanolic solution of hydrochloric acid (3.3N) are added to 6.52 g of product obtained in stage A in solution in 65 cm of ethanol and the mixture is heated for 24 hours at reflux. It is cooled to room temperature, concentrated to dryness under reduced pressure, the residue is taken up in water and extracted with ethyl acetate. 3.55 g of expected product are obtained. Analysis for C ₁₈ H _2g Cl ₃ N ₄ 0 ₂ Calculated: C% 49.2 H% 6.6 Cl% 24.2 N% 12.7 Found: 49.1 6.7 24.3 12.8

Preparation of 5- (diterbutoxycarbonyl guanidine) aminopentane used at the start of preparation 18.

Stage A: 3-benzyloxycarbonyl 1,3-thiazolidine 2-thione.

A 10 g of mercaptothiazoline in solution in 200 cm ³ of

. 3 methylene chloride, 12.9 cm of triethylamine cooled to 0 / -5 ^β C are added and 12 cm ³ of benzyl chloroformate dissolved in 60 cm of methylene chloride are added dropwise. The mixture is stirred for 3 hours at room temperature, poured into an ice-cold solution of N hydrochloric acid, the aqueous phase is extracted with methylene chloride, the organic phase is dried and concentrated to dryness; the residue is chromatographed on silica (eluent: hexane-ethyl acetate 7-3) and 17.9 g of expected product are obtained. F = 72'C.

REPLACEMENT SHEET Stage B: N-benzyloxycarbonyl 1,5-diaminopentane.

17.84 g of product obtained in Stage A are added in solution.

3 tion in 100 cm of methylene chloride to 16.4 g of 1,5-diaminopentane dissolved in 85 cm ³ of methylene chloride. The mixture is stirred for 3 hours, concentrated to dryness, the residue is chromatographed (eluent: ethanol-ammonia 99-1) and 10.5 g of the expected product are obtained.

Stage C; N-benzyloxycarbonyl 5 - [(diterbutoxycarbonyl) guani¬ dine) aminopentane. 10.5 g of product of stage B and 14.2 g of N, N'bis- (terbutoxycarbonyl) S-methylthioisourée in 75 cm of tetrahydrofuran and 5 cm of water are heated for 3 hours at reflux. The mixture is cooled, poured onto an aqueous sodium bicarbonate solution, extracted with methylene chloride, the organic phase is washed with water, dried and concentrated to dryness under reduced pressure. The residue is chromatographed on silica (eluent: hexane-ethyl acetate 7-3) and 10 g of the expected product are obtained. Stage D; 5- [(diterbutoxycarbonyl) guanidine) aminopentane. Hydrogenated for 5 hours, 10 g of product obtained in Stage C in ethanol in the presence of 1 g of activated carbon at 10% palladium. The catalyst is filtered, the filtrate is concentrated to dryness and 6.74 g of the expected product are obtained. PREPARATION 19: N- [6- (secbutyl) 2,4-dichlorophenoxy] acetyl 3-guanidine aminopropane hydrochloride.

Stage A: N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl 3 - [(di¬ terbutoxycarbonyl) guanidine aminopropane.

1.1 g of sodium bicarbonate are added to 3.93 g of N- [6- (sec-butyl 2,4-dichlorophenoxy) acetyl] 1,3-diamino propane hydrochloride prepared in preparation 20 in solution

3 in 50 cm of ethanol. It is heated 4 and a half hours at reflux and then left for 12 hours at room temperature. It is concentrated to dryness, diluted with water, extracted with methylene chloride, the organic phase is concentrated to dryness and 3.47 g of amine are obtained which is added to 3.63 g of N, N'bis- ( terbutoxycarbonyl)

3

S-methylthιoιsourée in 20 cm of tetrahydrofuran and 20 c of water. It is heated for three and a half hours at reflux, cooled to room temperature, poured onto an aqueous solution of

REPLACEMENT SHEET 10% sodium bicarbonate. Extraction is carried out with methylene chloride, the organic phases are combined, dried and concentrated to dryness under reduced pressure. After chromatography on silica (eluent: hexane-ethyl acetate 75-25), 2.4 g of expected product are recovered.

Stage B: N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl 3-guanidine aminopropane hydrochloride.

The procedure is carried out as in stage B of preparation 18 from 2.4 g of the product obtained above and 1.42 g of the expected hydrochloride are obtained.

IR_iÇHÇl ₃ l

NH: 3418 - 3335 - 3165 cm ^"1

C≈O: 1669 cm ^"1

C = C, C = N, CONH, amide II: 1620 - 1583 - 1565 - 1542 cm ^"1 PREPARATION 20: N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl diamino hydrochloride 1, 3-propane.

Stage A: N '- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl N-terbutoxycarbonyl diamino 1,3-propane.

The procedure is carried out as in stage A of preparation 7, starting from 1.68 g of the amine obtained as indicated in preparation B and 3.4 g of product obtained as in stage A of preparation 6. We obtain 3.7 g of expected product.

Stage B: N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl diamino 1,3-propane hydrochloride. The procedure is carried out as in Stage B of Preparation 18, starting from 3.69 g of the product prepared in Stage A and 2.9 cm of 3.3 N hydrochloric acid. 3.05 g of expected product is obtained.

Analysis for C ₁₅ H ₂₃ C1 ₃ N ₂ 0 ₂

Calculated: C% 48.7 N% 6.3 Cl% 28.8 N% 7.6 Found: 48.2 6.4 28.8 7.3

PREPARATION 21: N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl diamino 1,5-pentane hydrochloride.

Stage A: N '- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl N-terbutoxycarbonyl diamino 1,5-pentane. The procedure is carried out as in stage A of preparation 7 starting from 1.9 g of the amine obtained as indicated in preparation D and 3.32 g of product obtained as in stage A of preparation 6. We obtain 3 , 92 g of expected product.

OF SUBSTITUTION Stage B: N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl diamino 1,5-pentane hydrochloride.

The procedure is carried out as in Stage B of Preparation 18, starting from 3.88 g of the product prepared in Stage A and 3 cm of 3.3 N hydrochloric acid. 2.88 g of expected product are obtained.

IR fCHCl _j ):

NH: 3425 cm ^"1

C≈O: 1673 cm ^"1

C≈C, aromatic, CO amide II: 1610 - 1584 - 1565 - 1538 cm ^-1 PREPARATION 22: N- [6- (sec-butyl) 2,4-dichlorophenoxy] acetyl 4-ςruanidine .aminobutane hydrochloride.

The procedure is carried out as in stage B of preparation 18 starting from 4.49 g of product prepared in stage A of preparation 7 and

5 cm of 3.3N hydrochloric acid. The hydrochloride is obtained which is diluted in methylene chloride, dried and concentrated to dryness. After recrystallization from 1 * isopropyl ether, 2.4 g of the expected product are obtained.

PREPARATION 23: (2-Secbutyl 5-trifluoromethylphenoxyacetyl) triaza 1,6,10-decane dihydrochloride. Stage A: N- (2-sec-butyl 5-trifluoromethylphenoxyacetyl) 10-terbutoxycarbonyl triaza 1,6,10-decane.

Cool to 0 ^β / + 5 ^β C 3g of acid [5-trifluoromethyl 2-

. 3

(2-butyl) phenoxy] acetic in 30 cm of methylene chloride in the presence of 1.44 g of 2-mercapto thiazoline and 0.30 g of 4-dimethylaminopyridine. Was gradually added 2.47 g of dicyclohexylcarbodiimide in solution in 20 cm ³ of methylene chloride, kept stirred 1 hour at 0 ^e C then for 16 hours at room temperature. Filtered, the filtrate is concentrated to dryness and 5.46 g of residue are obtained which is chromatographed on silica (eluent: methylene chloride) and obtained

2.70 g of product which is dissolved in 30 cm3 of methylene chloride and 1.8 g of product prepared as in stage D of the preparation of the starting product of preparation 8 dissolved in 20 are added cm of methylene chloride. Maintained for 16 hours with stirring at room temperature, concentrated to dryness, and the residue is chromatographed on silica (eluent: methanol). 2.62 g of expected product are obtained. Stage B: (2-sec-butyl 5-trifluoromethyl- dihydrochloride)

REPLACEMENT SHEET phenoxyacetyl) triaza 1,6,10-decane.

Was heated for 3 hours at reflux 1.48 g of product obtained in stage A in 20 cm of a methanolic solution of 2N hydrochloric acid, concentrated under reduced pressure and collected 1.21 g of the expected product after drying under reduced pressure . Analysis for C ₂₀ H ₃₄ Cl ₂ F ₃ N ₃ O ₂

Calculated: C% 50.42 N% 7.19 Cl% 14.88 F% 11.96 N% 8.82 Found: 50.4 7.6 14.8 10.8 8.0 Acid preparation [ 5-trifluoromethyl 2- (1-methylpropyl) phenoxy] acetic used at the start of preparation 23. Stage A: (2-butenyloxy) 3-trifluoromethyl benzene.

Add 18 g of potassium carbonate to 15 c 3 of 3-

3 trifluoromethylphenol and 25 cm of 2-butanone, stir, then add 15.1 cm3 of 1-bromo 2-butene in 70 cm3 of 2-butanone and heat 1 hour and a half at reflux then stir 72 hours at room temperature. Then add 300 cm3 of water, extract with methylene chloride, dry and concentrate to dryness and collect 21.73 g of the expected product. Stage B: 5-trifluoromethyl 2- (1-methyl 2-propenyl) phenol. Heated for 2 hours at reflux 123.3 g of product prepared as in Stage A, chromatography on silica (eluent: n-hexane-diisopropyl ether 9-1 then 8-2) and recovered 16.95 g of the expected product. Stage C: 5-trifluoromethyl 2- (1-methylpropyl) phenol. 4.59 g of product from stage B is hydrogenated in 200 cm of ethanol in the presence of 0.50 g of activated carbon containing 10% palladium. Filtered, the filtrate is concentrated and 4.05 g of expected product is obtained. Stage D: [5-trifluoromethyl 2- (1-methylpropyl) phenoxy] ethyl acetate.

2.5 cm of ethyl bromoacetate are added to 4 g of

3 product obtained in stage C in 15 cm of dimethyl sulfoxide. 4 g of potassium carbonate are added and then heated to 80 ^β C for 2.5 hours. The reaction medium is poured into ice water, extracted with methylene chloride, dried and concentrated to dryness. 5.10 g of expected product is obtained. Stage E: [5-Trifluoromethyl 2- (1-methylpropyl)] acetic acid.

REPLACEMENT SHEET Stirred 45 minutes at room temperature 3 g of product obtained in Stage D and 8 cm ³ of 2N sodium hydroxide in 10 cm ³ of ethanol. Concentrate then dilute with water, extract with methylene chloride, acidify to pH ≈ 1 then extract with ethyl acetate, wash with water, dry and remove the solvents under reduced pressure. 1.24 g of expected product is obtained after washing with hexane. F = 96 "C.

PREPARATION 24: N- (3-methoxy 4-hydroxyphenoxyacetyl) diamino 1,4-butane and its hydrochloride. Stage A: N- (3-methoxy 4-benzyloxyphenoxyacetyl) N-terbutoxy¬ carbonyl diamino 1,4-butane.

The procedure is carried out as in stage A of preparation 23 using at the start 2.8 g of 4-benzyloxymethoxyphenoxy acetic acid, 115 mg of dimethylaminopyridine, 2 g of dicyclohexylcarbodimimide and 1.8 g of N-terbutoxycarbonyl diamino 1,4-butane. 2.4 g of expected product are obtained after chromatography on silica (eluent: chloroform-acetone-cyclohexane 1-1-2). Stage B: N- (3-methoxy 4-hydroxyphenoxyacetyl) N • -terbutoxycarbonyl diamino 1,4-butane. 2.4 g of product prepared in Stage A are hydrogenated in 100 cm3 of ethanol with 50 cm3 of cyclohexene in the presence of 2.4 g of activated carbon containing 10% palladium. The mixture is refluxed for 3 hours, cooled, filtered and the filtrate is concentrated to dryness. 1.96 g of expected product are obtained. Stage C: N- (3-methoxy 4-hydroxyphenoxyacetyl) diamino 1,4-butane and its hydrochloride.

The operation is carried out as in stage B of preparation 1 from 1.96 g of product obtained above. 1.56 g of hydrochloride are obtained, then 1.28 g of the expected base after chromatography on silica (eluent: methanol-ammonia 98-2). F »100 ^β C.

IR_CÇHÇ! ₃ 1:

OH-NH: 3303 cm ^"1

C = 0: 1652 cm ^"1 NH ₂ , aromatic, amide II: 1612 - 1574 - 1545 - 1491 cm ^{" 1} Preparation of 4-benzyloxy 3-methoxyphenoxy acetic acid used at the start of preparation 24. Stage A; 4-benzyloxy 3-methoxyphenol.

REPLACEMENT SHEET 24.2 g of 4-benzyloxy 3-methoxy benzaldehyde (Beilst. 8 II. 283) are dissolved in 100 cm of acetic acid, a mixture of 25 cm of peracetic acid and 50 cm ³ of acetic acid is added without exceeding 45 "C and stirred for 18 hours at +40 ^β C. The residue is concentrated to dryness, chromatography on silica

(eluent: hexane-ethyl acetate 8-2) and obtains 9.1 g of the expected product. F = 84 ^β C

Stage B: 4-benzyloxy 3-methoxyphenoxy ethyl acetate.

The procedure is carried out as in stage C of preparation 16 from 2.76 g of product prepared in stage A, 1.82 g of carbonate

3 of potassium, 15 cm of methyl ethyl ketone and 1.6 cm of ethyl bromo-acetate. The extraction is carried out using methyl ethyl ketone. The organic phase is concentrated to dryness. 3.9 g of crude product are obtained which is chromatographed on silica (eluent: hexane-ethyl acetate 8-2). 3.6 g of expected product are obtained. F = 58 "C. Stage C: 4-Benzyloxy 3-methoxyphenoxy acetic acid.

The operation is carried out as in stage D of preparation 16, starting with 3.2 g of product obtained above, 5 cm of 2N soda then 5 cm of hydrochloric acid. and obtains 2.85 g of the expected product.

PREPARATION 25: N- (2,4-dichlorophenoxyacetyl) N '- [1- (3-indol-acetyl)] diamino 1,4-butane.

The procedure is as in preparation 23 stage A starting from 2 g of 3-indolyl acetic acid, 0.135 g of dimethylaminopyridine, 2.35 g of dicyclohexylcarbodiimide and 3.32 g of N- (2,4-dichlorophenoxyacetyl) diamino 1,4-butane obtained from the product prepared in preparation 9. Obtained, after chroma¬ toography on silica (eluent: hexane-ethyl acetate 6-4) then methanol, 3.4 g of the expected product. F = 128 ^β C.

PREPARATION 26: N- (7-hydroxy coumarinyl 4-acetyl) diamino 1,4-butane hydrochloride.

Stage A: N-terbutoxycarbonyl N '- (7-hydroxy coumarinyl 4-acetyl) diamino 1,4-butane. 8.9 g of 7-hydroxy coumarin 4-acetic acid in 135 cm of tetrahydrofuran are added to a suspension comprising 12.64 g of 2-chloro N-methyl pyridinium iodide in 135 cm ³ of tetrahydrofuran. Then added 7.52 g of N-terbutoxy-

RE SHEET carbonyl diamino 1,4-butane obtained as in Preparation A in 100 cm ³ of tetrahydrofuran and then 13.5 cm ³ of triethylamine and heated for 6 hours at reflux then maintained under stirring for 16 hours at room temperature. Filtered, the filtrate is concentrated, the residue is taken up in water, the crystals are dried and purified by chromatography on silica (eluent: ethyl acetate-n-hexane 8-2). 4.46 g of expected product are obtained. F = 171 "C.

Stage B: N- (7-hydroxy coumarinyl 4-acetyl) diamino 1,4-butane hydrochloride.

The procedure is as in Example 8 stage B from 4.32 g of product obtained in stage A and 7.5 cm ³ of 2.2N hydrochloric acid. 2.67 g of expected product is obtained after recrystallization from methanol. F = 220 ^β C. Analysis for ^c i5 ^H τq ^cl - ^N 2 ⁰ 4

Calculated: C% 55.13 H% 5.86 Cl% 10.85 N% 8.57 Found: 54.9 5.9 11.2 8.4 Preparation of 7-hydroxy coumarin 4-acetic acid used in start of preparation 26. agitation is carried out for 1 hour at room temperature 84 g of citric acid and 112 cnr3 of concentrated sulfuric acid, gradually heated to 70 ^β C, maintained for 35 minutes, cooled to 0 ° C. and added 34, 56 g of 1,3-benzene diol and 44.8 cm of concentrated sulfuric acid. Maintained for 16 hours at 0 ^β C, poured onto ice, wring the crystallized product, dry under reduced pressure. After recrystallization from water, 22.77 g of expected product are obtained. F = 210 "C.

PREPARATION 27: N - [(2-methyl 6-indolyloxy) acetyl] 1,4-diamino butane hydrochloride. Stage A: N- (tert-butoxycarbonyl) N '- [(2-methyl 6-indolyloxy) acetyl] 1,4-diamino butane.

1.07 g of sodium hydride suspended in 50% oil is gradually added in a solution containing 3.28

. 3 g of 6-hydroxy 2-methyl mdole in 50 cm of dimethylformamide. The suspension thus stirred is stirred for 1 hour. A solution containing 6.5 g of N ¹ - (tert-butoxycarbonyl) N- (chloroacetyl) 1,4-diamino butane, obtained as indicated in the preparation of Preparation 3, is slowly introduced.

REPLACEMENT SHEET 3, and 60 cm of dimethylformamide. The reaction medium is stirred at 90 ° C for 5 hours, then 16 hours at room temperature. The suspension obtained is brought to dryness. 13.08 g of a product are obtained which is chromatographed on silica eluting with a hexane-ethyl acetate mixture (30-70). 4.98 g of the desired product are obtained, melting at 132 "C. Stage B: N - [(2-methyl 6-indolyloxy) acetyl] 1,4-diamino butane hydrochloride.

. ₃

9.9 cm of a 2N hydrochloric solution in ethanol are added to a suspension containing 4.96 g of the compound obtained in the preceding stage in 50 cm of ethanol. The reaction mixture is kept under stirring for 1 hour at reflux. The solution obtained is brought to dryness. 5.70 g of crude product are obtained which is taken up in 20 c of acetonitrile. 3 cm of propylene oxide are added. The reaction mixture is kept under stirring for 30 minutes. The reaction mixture obtained is concentrated. The product obtained is pasted in isopropyl ether, drained and dried. We then obtain 3.88 g of the desired product melting at 129 ^β C. PREPARATION 28: N- (3-trifluorométhylphénoxyacétyl) N- [l- (2-trifluoromethyl-3 indolacétyl)] diamino 1 -butane.

The procedure is carried out as in stage A of preparation 26, starting from 6.01 g of 2-chloro N-methyl pyridiniu iodide, 4.77 g of 3- (2-trifluoromethyl indolyl) acetic acid, 5.51 g of N- (3-trifluoromethylphenoxyacetyl) 1,4-diamino butane obtained from the hydrochloride prepared in preparation 4 and 6.55 cm ³ of triethylamine. After chromatography on silica (eluent: ethyl acetate), 4.85 g of expected product are obtained.

Analysis for ^C ₂ 4 ^H ₂₃ ^F ₆ ^N ₃ ° ₃ Calculated: C% 55.92 H% 4.49 F% 22.11 N% 8.15

Found: 55.70 4.5 21.8 8.1

Preparation of 3- (2-trifluoromethylindolyl) acetic acid used at the start of preparation 28.

Stage A: 5,5,5-trifluoro 4-oxo 3-ethoxycarbonyl ethyl pentanoate.

200 g of diethyl succinate and 82 g of ethyl trifluoroacetate are mixed and 13.2 g of

3 sodium and 200 c of ether. We heat 18 hours at 80 "C, pour the reaction medium on 200 cm ³ of ice-cold ION sulfuric acid. Decanted, dried, concentrated and the expected product is obtained, which is used as it is for the next stage. Stage B: 5,5,5-trifluoro 4-ethyl oxo pentanoate. ^Β heated to 180 C for 3 hours 45 g of product prepared in Stage A, 10.3 g of boric acid and 1 g of para-toluenesulphonic acid. Poured onto ice, extracted with ethyl acetate, decanted, dried and concentrated under reduced pressure. The residue is distilled and 10.8 g of the expected product are obtained. stage C: 3- (2-trifluoromethylindolyl) ethyl acetate.

A solution of 5.9 g of phenylhydrazine in 10 cm of ethanol is added to 10.8 g of product prepared in stage B in

3 ₃ solution in 15 cm of ethanol, then 2.74 cm of 2N hydrochloric acid in solution in 1 * ethanol. Stirred for 3 hours at 20 ° C., concentrated under reduced pressure and obtained 17.6 g of intermediate which is taken up in 50 cm of ethanol, cooled to +4 ^β C and treated with a stream of acid hydrochloric gas. The mixture is heated for 24 hours at boiling point, filtered, the filtrate is concentrated, the residue is chromatographed on silica (eluent: cyclohexane-isopropyl ether 7-3) and 6.9 g are obtained. of expected product. F = 86 * C. Stage D: 3- (2-Trifluoromethylindolyl) acetic acid.

2.15 g of sodium bicarbonate are added in 3 times in a solution of 3.08 g of the product obtained above in 20 cm ³

₃ of methanol and 10 cm of water and stirred for 24 hours. The solution is concentrated, the residue is taken up in 20 cm ³ of water, acidified with hydrochloric acid, extracted with ethyl acetate, dried and concentrated to dryness. The residue is chromatographed on silica (eluent: hexane-ethyl acetate-acetic acid 78-20-2) and 2.6 g of the expected product are obtained. F = 146 ^β C. PREPARATION 29: 1,10- (3-indolacetyl) 1,6,10-triaza decane.

By operating as indicated above from the appropriate acid and amine, the expected product was obtained. Analysis for ^C ₂₇ * ^{: i} ₃₃ ^1J 5 ⁰ 2

Calculated: C% 70.55 H% 7.23 N% 15.21

Found: 70.3 7.4 15.0

Preparation A: N- (tert-butoxycarbonyl) 1,4-diamino butane.

FE ILLE DE REMP To a solution of 320 g of 1,4-diamino butane, in 2,800 cm of methylene chloride, cooled to +5 "C, 400 g of di oxide are added in 1 hour at 0 ° / ⁺ 5 ^β C -tert-butoxycarbonyl

₃ dissolved in 2000 cm of methylene chloride. The mixture is stirred for 1 hour at 20 ^β C and the insoluble material is filtered. The filtrate is evaporated to dryness under reduced pressure and the oil obtained (363.1 g) is chromatographed on silica (eluent: flugene (113) - methanol (9-1) then methanol, then methanol-ammonia

(96-4)). 203.6 g of expected product are obtained. NMR spectrum (CDC1 ₃ ): tBu - 87 Hz

ÇH ₂ NH ₂ - 162 HZ

CH ₂ NHCO - 186 Hz

C = O - 280 HZ CH ₂ (central) - 89 Hz

Preparation B: N- (tert-butoxycarbonyl) 1,3-diamino propane.

_ ₃

To a solution of 36 cm of 1,3-diammopropane, in 160 cm of methylene chloride is added at + 5 ° C, without exceeding + 10 ° C, a solution of 46 g of di-tert-dicarbonate

3 butyl in 120 cm of methylene chloride, stirred

16 hours at 20 ^β C, filters the insoluble matter and evaporates _. the dry filtrate under vacuum. 63 g of residue are obtained, chromatography on silica (eluent: methanol at 2% ammonia). 23 g of expected product are obtained. F <60 "C. Preparation C: 3 - [(tert-butoxycarbonyl) amino] 1-bromopropane. Stage A: 3- [(tert-butoxycarbonyl) amino] 1-propanol.

To a solution of 7.5 g of 3-amino 2-propanol in 75 cm

3, water and 75 cm of tetrahydrofuran, 21.8 g of di-tert-butyl dicarbonate dissolved in

₃

50 cm of tetrahydrofuran. After 2 hours of stirring at 20 ° C., the mixture is evaporated to dryness under reduced pressure, the oil residue is taken up with 150 cm3 of ethyl acetate, the solution is washed with two faiths. 30 cm3 0.5 M acetic acid, then with water, evaporated to dryness under vacuum. 15.4 g of expected product are obtained. Stage B: 3- [(tert-butoxycarbonyl) amino] 1-bromopropane.

To a solution of 9 g of product obtained in stage A in

REPLACEMENT SHEET 120 cm ³ of tetrahydrofuran and 19.7 g of triphenyl phosphine, 25 g of carbon tetrabromide dissolved in 50 cm ³ of acetonitrile are added slowly, while maintaining the temperature between 20 and 25 ° C. The mixture is stirred for 15 hours, the insoluble material is filtered and the filtrate is concentrated to dryness under reduced pressure. The residue is chromatographed (45 g) on silica (eluent: hexane-ethyl acetate (8-2)). 9.4 g of expected product are obtained. M = 40 ° C. IR spectrum (CHC1 ₃ ):

= C-NH 3460 cm ^"1

CO (carbamate) 1708 cm ^"1 secondary amide 1505 cm Me t.Bu 1368 cm ^{" 1} Preparation D: N-tert-butoxycarbonyl diamino 1,5-pentane. 54 cm ³ of 1,5-diamino pentane in 200 cm of methylene chloride are cooled to + 5 ° C. then 50 g of diterbutyl dicarbonate dissolved in methylene chloride are added. Stirred 15 minutes at 0 ^β C, allowed to return to room temperature and maintained under stirring for 16 hours. Filtered, the filtrate is concentrated to dryness and 38 g of crude product are obtained which is chromatographed on silica (eluent: methanol-ammonia 98-2). 18.31 g of expected product are collected.

Biological activity

Tests on RMB7 tobacco a) Cell multiplication (calogenesis).

The RMB7 Hybrid Tobacco cuttings are grown in a peat-gravel mixture and kept in an air-conditioned room (photoperiod: 16 hours, day temperature: 26 ° C, night temperature: 21 "C, relative humidity: 60%) The medium (medium 1) is that of Murashige and Skoog ("MS") supplemented with indolacetic acid (2 mg / 1) and benzylaminopurine (0.2 mg / 1). The products are dissolved in a matrix then diluted in medium 1 (final matrix concentration: 0.27%). The products are tested at concentrations of 10 - 5, 10 - 4 and 10 - 3 M. Disks (diameter: 8 mm ) are

REPLACEMENT SHEET cut from young leaves previously sterilized with a solution of calcium hypochlorite (30 g / 1) and then deposited on the surface of the medium thus prepared (medium 1), after gelling thereof. The tubes containing the explants are placed in a culture chamber, under the same climatic conditions as the cuttings. The evolution of the weight of the explants is followed for 5 weeks. The controls, placed on the middle 1 alone, survive without developing.

The activity is measured in% efficiency compared to a control 2 treated under the same conditions with a mixture containing 2 mg / 1 of naphthylacetic acid (ANA) and 0.2 mg / 1 of benzyladenopyrine (BAP).

Efficacy = mass of the explant treated with product _Q mass of the explant from control 2 under these conditions after 5 weeks the RMB7 tobacco gives a Cal of approximately 1200 mg ± 200. b) Budding (caulogenesis).

The tests are carried out as described above, except that the medium (medium 2) consists of "MS" to which are added indolacetic acid (2 mg / 1) and benzylaminopurine (5 mg / 1). In medium 2 alone, the explants do not form buds. The activity of the products is evaluated by visual control of the formation of buds on the discs. Efficiency is measured according to the following criteria:

0 - no buds (no roots) 25 - Very small buds at 10 - 3M (no roots)

50 - Small buds at 10 -3 M or very small buds at 10-4 or 10 —5 (no roots) 75 - Buds at 10 —3 or small buds at 10—4 or 10—5 M 100 - Buds at 10 -3 and a. 10-4 or 10-5 M

(ditto for the roots). c) Rhizogenesis.

The tests are carried out as described above, except that the medium (medium 3) consists of "MS" to which is added indolacetic acid (2 mg / 1). In medium 3 alone, the explants do not form roots. The activity of the products is evaluated by visual control of the formation of

REPLACE ENT roots on discs.

Efficiency is measured according to the following criteria: 0 - no buds (no roots) 25 - Very small buds at 10 - 3M (no roots) 50 - Small buds at 10 -3 M or very small buds at 10-4 or 10 —5 (no roots)

75 - Buds at 10 -3 or small buds at 10-4 or 10-5 M

100 - Buds at 10 ~ ³ and 10 ~ ⁴ or lθ ^"5 M

(ditto for the roots). The results obtained are as follows:

Cal Caulogenesis Rhizogenesis

Product of preparation 4 87 100 100 Product of preparation 9 35 0 0 Product of preparation 11 62 0 25 Product of preparation 15 67 0 25 Product of example 24 24 75 25 Product of example 27 32 50 75 Preparation product 15 67 0 25

REPLACEMENT SHEET

Claims

1) As plant growth regulators, the compounds of formula (I): O

^R l ^"CH 2 ^" ^ ^"NH" ( ^W ) ^"NHZ t ¹ )

in which, R. represents: - either an ArO- radical in which Ar represents an aryl radical containing up to 14 optionally substituted carbon atoms or an optionally substituted heteroaryl radical or an optionally substituted heterocyclic radical,

- Either an aryl or polyaryl radical condensed or not or a heterocyclic radical optionally substituted.

W represents:

- or a radical (CH ₂ ) n, in which n represents an integer which can vary from 2 to 6,

- or a radical (CH ₂ ) n ₂ NY (CH ₂ ) n ₃ in which n ₂ and n ₃ identical or different represent an integer which can vary from 2 to 6 and Y represents a hydrogen atom or a radical alkyl containing up to 12 carbon atoms or an aryl radical containing up to 14 carbon atoms optionally substituted or an arylalkyl radical containing up to 18 carbon atoms optionally substituted, or a C0 ₂ alkyl radical in which the alkyl radical contains up to 12 carbon atoms, or a COR ₂ radical in which the radical R ₂ represents an alkyl, alkenyl or alkyyl radical containing up to 12 carbon atoms or an aryl radical containing up to 14 carbon atoms or an arylalkyl radical containing up to 18 optionally substituted carbon atoms or an optionally substituted heterocyclic radical and Z represents: - either a hydrogen atom,

- or a radical -C = NH

NH ₂

REPLACEMENT SHEET - either a radical in which R ′ ₂ represents an alkyl radical containing up to 12 carbon atoms, or an arylalkyl radical containing up to 18 carbon atoms,

- or a C0 ₂ alkyl radical in which the alkyl radical contains up to 12 carbon atoms,

- either a CO, arylalkyl radical in which the aryl¬ alkyl radical contains up to 18 carbon atoms, - or a COR " ₂ radical in which R" ₂ can take one of the values indicated above for R ₂ ,

- or a radical -CH ₂ R ₃ in which R ₃ represents an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic radical or can take the values indicated above for R- ^

- or a radical -COCH ₂ R ' ₃ in which R' ₃ can take one of the values indicated above for R ₃ , on the condition that Z does not represent a hydrogen atom, if W represents a radical ( CH ₂ ) ₃ and R ₁ represents a 2,4-dichlorophenoxy radical as well as the addition salts with organic or inorganic acids of the compounds of formula (I). 2) As plant growth regulators, the compounds of formula (I) as defined in claim 1 in which the aryl, heteroaryl, arylalkyl and heterocyclic radicals are optionally substituted by one or more substituents chosen from the group consisting of hydroxyl radicals, halogen atoms, alkyl, alkenyl and alkynyl radicals containing up to 14 carbon atoms, CF ₃ radicals, OR " ₃ radicals in which R" ₃ represents an alkyl radical containing up to with 12 carbon atoms or an arylalkyl radical containing up to 18 carbon atoms, the COalkyl, Si (alkyl) ₃ , SO ₂ alkyl radicals in which the alkyl radical contains up to 12 carbon atoms, and the radicals S0 ₂ aryl in which the aryl radical contains up to 14 carbon atoms, the different radicals being able to form with the atoms to which they are linked rings 0-CH ₂ -0, as well as their ad salts edition with organic or mineral acids. 3) As plant growth regulators, the compounds of formula (I) as defined in claim 1 or 2 in which W represents a radical (CH ₂ ) ₃ , (CH ₂ ) ₄ or (CH ₂ ) ₅ as well as their addition salts with organic or mineral acids.

4) As plant growth regulators, the compounds of formula (I) as defined in claim 1 or 2 in which W represents a radical (CH ₂ ) n ₄ NH (CH ₂ ) n ₅ in which n ₄ and n ₅ identical or different represent the numbers 3, 4 or 5 as well as their addition salts with organic or mineral acids.

5) As plant growth regulators, the compounds of formula (I) as defined in any one of claims 1 to 4 in which Z represents a hydrogen atom, or a C0 ₂ alkyl radical in which the alkyl radical contains up to 12 carbon atoms as well as their addition salts with organic or mineral acids.

6) As plant growth regulators, the compounds of formula (I) as defined in any one of claims 1 to 5 in which Z represents a radical C≈NH, or a radical -Ç = NC0 R '

1 2 2

NH ₂ NHC0 ₂ R » ₂

R ' ₂ retaining the same meaning as in claim 1, as well as their addition salts with organic or mineral acids.

7) As plant growth regulators, the compounds of formula (I) as defined in any one of claims 1 to 6 in which R. represents an ArO radiol- in which Ar represents an optional aryl radical - Lement substituted as well as their addition salts with mineral or organic acids.

8) As plant growth regulators, the compounds of formula (I) as defined in claim 7 in which Ar represents the radical:

as well as their addition salts with organic or mineral acids.

9) As plant growth regulators, the compounds of formula (I) as defined in any one of claims 1 to 6 in which R _χ represents a radi¬ cal:

as well as their addition salts with organic or mineral acids.

10) As plant growth regulators, the compounds of formula (I) as defined in any one of claims 1 to 6 in which R represents a radi¬ cal:

as well as their addition salts with organic or mineral acids.

11) As plant growth regulators, the compounds of formula (I) as defined in any one of claims 1 to 6 in which R. represents a radiol:

as well as their addition salts with organic or mineral acids.

12) As plant growth regulators, the compounds of formula (I) as defined in claim 6, the names of which follow:

- N - [(4-hydroxy 3-methoxy phenoxy) acetyl] 1,4-diamino butane

- N- [(2-methyl 6-indolyloxy) acetyl] 1,4-diamino butane

- N- [(3-trifluoromethyl phenoxy) acetyl] 1,4-diamino butane

REPLACEMENT SHEET - N - [(3-trifluoromethyl phenoxy) acetyl] N '- [1- (3-indolyl) acetyl] 1,4-diamino butane

- N - [(2,4-dichloro phenoxy) acetyl] 1,4-diamino butane and their addition salts with organic or mineral acids.

13) The phytosanitary compositions containing as active principle at least one growth regulator defined in any one of claims 1 to 11.

14) The phytosanitary compositions containing as active principle at least one growth regulator defined in claim 12.

REPLACEMENT SHEET