FR2526423A1 - NOVEL UNSATURATED AMINES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

THE INVENTION RELATES TO COMPOUNDS OF FORMULA (CF DRAWING IN BOPI) IN WHICH R REPRESENTS A GROUP (CF DRAWING IN BOPI) OR R AND R ARE HYDROGEN, A HALOGEN, CF, ALKYL, ALCOXY, S MEANS 3, 4 OR 5, X MEANS O, S, CH, OCH, SCH OR NR OR R IS HYDROGEN OR ALKYL, R IS HYDROGEN OR ALKYL, OR R AND R REPRESENT (CF DRAWING IN BOPI) OR P MEANS 1, 2 OR 3, R AND R ARE HYDROGEN OR ALKYL AND R REPRESENTS A HALOGEN, ACETAL GROUP, THIOACETAL, HALOGENOALCENYL, HALOGENOCYCLOALKYL, ALKYLCYCLOALKYL OR ALKYL SUBSTITUTE (SIGNIFICANTLY 3 - OR RALLY 4 - OR R - AND R) OR 5. THESE COMPOUNDS MAY BE USED AS CHEMOTHERAPEUTIC AGENTS, ESPECIALLY AS ANTIMYCOTICS.

Description

The subject of the present invention is new unsaturated amines, their

  PREPARATION AND THEIR USE IN THERAPEUTICS, AS ACTIVE INGREDIENTS OF MEDICAMENTS The invention relates more particularly to the amines of formula I

R 1 R 4

R 2 C N CH 2 CH = CH C C R 8 ()

  R 3 in which a) R 1 represents a group of formula I Ia, I Ib or I Ic,

RF R R

R 6 9 (CH C) 56

  (I Ia) (I Ib) (I Ic) in which R and R each independently represent a hydrogen or a halogen or a group;

  trifluoromethyl, lower alkyl or lower alkoxy

  s is 3, 4 or 5 and X is -O-, -S-, -CH 2, -OCH 2, SCH 2 or -N (R 7) o R 7 is hydrogen or an alkyl group lower, and R represents hydrogen or a lower alkyl group, or else

  R 1 and R 2 represent, with the adjacent carbon atom,

  to which they are attached, a group of formula I Id

(CH) p-

  Wherein p is 1, 2 or 3, R 3 and R 4 are each, independently of one another, hydrogen or a lower alkyl group and

  R 8 represents a halogen, a group-acetal or thio-

  acetal optionally substituted with lower alkyl, a haloalkenyl group, a

  halogenocycloalkyl, a lower alkyl group

  cycloalkyl, or an alkyl group substituted by lower alkoxy,

  lower alkylthio, lower haloalkyl, aceto

  tal, thioacetal, cyano, formyl or hydroxy, the carbon atom in a of the triple bond must not have a hydroxy group, or b) R 3 and R 4 together form a group - (CH 2) u or means 3 , 4 or 5, R 1 represents a group of formula I Ia, Ib or Ic, R 2 represents hydrogen or a lower alkyl group and R 5 to R 8 have the meanings given above,

  in the free base state or in the form of an additive salt

acid.

  According to the process of the invention, to prepare the compounds of formula I a compound of formula III R 1 is reacted

R 2 C NH R 4

R 3 (III)

with a compound of formula

A 5 CH 2 CH = CH C C R 8

  in which a functional group optionally

  is in protected form, formulas in which R 1, R 2, R 3, R 4 and R have the meanings given above, and A represents an eliminable group, / present / and, if necessary, eliminates any protecting group The process may be carried out according to the methods

  classics, for example in a solvent, inert under the conditions

  of the reaction, such as a lower alkanol such as

  ethanol, possibly mixed with water, a hydro-

  aromatic carbide such as benzene or toluene, a cyclic ether such as dioxane, or a dialkylamide of carboxylic acid such as dimethylformamide is carried out at a temperature between room temperature and the boiling point of the reaction mixture,

  preferably at room temperature Group A elects

  shabby can be for example a halogen as per

  chlorine or bromine, or a sulphonyl group

  organic oxy containing from 1 to 10 carbon atoms, for example an alkylarylsulfonyloxy group such as p-toluenesulfonyloxy or an alkylsulfonyloxy group such as methanesulfonyloxy. When appropriate, the reaction is advantageously carried out in the presence of an acid-accepting agent such as for example an alkali metal carbonate such as sodium carbonate or potassium carbonate when

  this is appropriate, the possible functional groups

  contained in the starting material may be protected by suitable protecting groups which may, after the reaction, be removed according to

known methods.

  The compounds of formula I thus obtained

  can then be isolated and purified according to the

usual methods.

  The compounds of formula I can be recovered according to the known methods, in the form of

  free base or as an acid addition salt.

  Free bases can be transformed according to

  known methods in salts, and vice versa.

  The compounds of formula I and their

  mediates can be obtained as mixtures of different cis / trans isomers which can be

  separated according to known methods.

  Unless otherwise indicated, the alkyl radicals are preferably straight or branched chain containing from 1 to 12 carbon atoms, especially from 1 to 12 carbon atoms.

  to 8 carbon atoms, especially 6 and especially

  A particular group of such alkyl radicals includes alkyl radicals having

  2 or more carbon atoms The lower alkyl groups

  present as substituents in a substitute

  are linear or branched and preferably contain 1 to 4 carbon atoms, especially

  1 or 2 carbon atoms The alkenyl con-

  preferably contain 3 to 6 carbon atoms, especially 3 or 4 carbon atoms such as for example the allyl or propenyl group. The cycloalkyl groups are preferably cyclohexyl, cyclopentyl or cyclopropyl. Halogen refers to fluorine,

chlorine, bromine or iodine.

  The acetals and thioacetals groups preferably contain

  1 to 4 carbon atoms, especially 1 or 2 carbon atoms in their respective alkyl radicals,

  or can also be cyclic.

  The starting materials of formula III are partially new and can be prepared by reacting a compound of formula V R 2 C Hal (V)

R

with a compound of formula VI

R 14, H 2 (VI)

  formulas in which R 1, R 2, R 3 and R 4 have the same

  meanings previously given.

  The starting materials of formula IV are partially new and can be prepared, for example, according to the following reaction scheme: ## STR2 ##

R 8 C CH CH = CH 2 + PA 3 (HA) IV

  OH in which R 8 and A have the given meanings

  previously and Me represents the cation of a metal.

  The reaction conditions are those customarily used for such reactions, the various intermediate products being able, where appropriate, to be reacted subsequently without prior isolation.

  isolate the intermediate products according to known methods.

  Other starting materials and intermediates are known or can be prepared

according to known methods.

  The compounds of formula I possess

  interesting chemotherapeutic properties and can

  therefore be used as drugs.

  In particular, the compounds of Formula I exert an antimycotic action as shown by invitro serial dilution tests on various families and types of fungi, including Trichophyton spp., Aspergillus spp., Microsporum spp., Sporotrix schenkii, and Candida spp. concentrations included by

example between 0.003 and 50 μg / ml.

  The anti-mycotic activity of the compounds of formula I was also demonstrated in vivo in the experimental model of dermal mycosis in guinea pigs 24 hours after infection, the substance to be tested is administered daily to animals for 7 days, or by local application by rubbing the infected place, the substance to be tested being in this case in polyethylene glycol, or orally, the activity against Candida, presented especially by the compounds of formula I in which R 1 is a group of Formula Ib, was demonstrated in vivo using conventional experimental models, such as the model of disseminated infection or infection.

  intravaginal / intrauterine in mice or rats.

  A marked anti-mycotic activity is observed when the compounds of formula I are applied topically to a concentration of, for example, between 0.01 and 0.2%. Oral activity has been observed in vivo on guinea pig trichophytosis. Has

  doses for example between 2 and 70 mg / kg.

  Thanks to these properties, the compounds of formula I can be used therapeutically as chemotherapeutic agents, in particular as anti-mycotic agents. For this use, an appropriate daily dose will be between about 2000 mg of active substance that will be advantageously administered. in unit dose form each containing between about 17.5 and 1000 mg of substance

  active 2 to 4 times a day, or in free-form

delayed ration.

  The compounds of formula I can be used in the free base state or in the form of a salt

  addition of chemically acceptable acid

  These salts have the same order of activity as the corresponding free bases. The appropriate salts are, for example, the hydrochloride,

  hydrogenofumarate or naphthalene-1,5-disulfonate.

  The invention therefore relates to the compounds of formula I, in the free base state or in the form of a chemically acceptable acid addition salt, for use as medicaments, in particular as chemotherapeutic agents. ,

including anti-mycotics.

  The invention also relates to a medicament containing, as active ingredient, a compound of formula I in the free base state or as a chemically acceptable acid addition salt. For their therapeutic use, the compounds of formula I may be admixed with chemotherapeutically acceptable diluents and carriers and, optionally, other excipients.

  oral form of tablets or capsules.

  The compounds can also be applied topically, for example in the form of ointments or creams,

  parenteral or intravenous

  of the active substance depends on the compound used, the treatment envisaged, the type of formulation, etc. In general, satisfactory results are obtained when the formulations intended for application

  topically contain the active ingredient at a concentration

  for example between 0.05 and 5% by weight,

  in particular between 0.1 and 1% by weight.

  Such compositions also make

part of the invention.

  The preferred meanings of the substituents present in the compounds of formula I are R = a) I b) I Ib R 2 and R 3 = HR 4 = lower alkyl, especially methyl R 5 and R 6 = a) hydrogen b) halogen, especially chlorine R 8 = a) lower alkyl substituted by alkoxy or alkylthio

  (b) an acetal or thioacetal group (

  substituted by lower alkyl)

as well as their combinations.

  The preferred compounds are those in

  which the double bond adjacent to the nitrogen atom has

the configuration (E) trans.

  A particularly preferred compound is

  (E) -N- (1-Naphthyl-methyl) -N-methyl-6-ethoxy-6-methyl

  hept-2-ene-4-ynylamine. The following examples illustrate the present invention without in any way limiting its scope.

  all temperatures are in degrees Celsius.

Example 1

  (E) and (Z) -N-methyl-N- (1-naphthylmethyl) -6-methoxy-6-

methyl-hept-2-ene-4-ynyl-amine

  To a mixture of 16.1 g of N-methyl- (l-

  naphthyl) methylamine, 16.5% of sodium carbonate and 100 ml of dimethylformamide,

  drop a solution of 16.9 g of 1-bromo-6-methoxy-6-

  methylhept-2-ene-4-yne (E / Z mixture) in ether.

  After stirring overnight, the reaction mixture is filtered and the solvent is removed under reduced pressure. The evaporation residue is partitioned between a saturated aqueous solution of sodium bicarbonate and dichloromethane, the organic phase is dried, concentrated and chromatography on silica gel

  (eluent: 4: 1 mixture of toluene and ethyl acetate).

  We obtain first the isomer (E) then the isomer (Z)

in the form of oils.

  By proceeding in a similar manner or as described above, the following compounds of formula I are obtained in which R 2 and R 3 denote hydrogen.

and R 4 is a methyl group.

(Table see following pages)

  Example R 1 R 8 Conf 4 Data ph'y-

guraiion sico-chimicues 2 3 E nuile

-C-OCH 3

, s eH c

4 E

z

6 CH

-C-OCH 2 CH 3 E

CH 3

7 3

-C-OCH CH

1 2 3

-CH 3 '_

E 154-156

hydrochloride)

-CH -S-CH CH E il-

2 2 3

1 1 he lo z He-

l H

12 the 3 1 1 E il-

-C'rl -S-CH 3 i

BOARD

he- he- z oil he

R T Physical data

  EXAMPLE R _______________________________________ Chemicals C 2 H 5 E Oil 13 'O c 2 H 5

14 H 3 E F 1317

-C-CH CH N 6317

  Ca I 2 (dhlorliydr 3; te); Z oil 16 E -'n

17 -i-Z-

18 E

___-- CH 3-C

19 H 3 E

-C-CH -CHO

C 3

C 3 E

-CH-CH 2 CH 2 OH

21 "

/ c 2 E -CH / C 2

22 II E

1 _________________I F = 145-148 o

I (hydrochloride

  R R Con f 1 Physical Data: Example 1 8 gu ra t i ofnich 1 m i g ues CH

23 3 CH

2 E-F = 150-155 '

-C 12 C (chlorhydrate) 24 z oil

F = 130-1350

issued (chiorhydratel 26 z-oil

27 E

s 28 z

29 H 3

_CH 2 CH 2 OCH 3 E

CH 3 z H

31 3

-C-OCH 3 E

3 '32 z -SCH

-CH 3 E

-SCH 3

m i, 1 2

-CH-CH

  '-s C 3 Jq E -il - il- il- z -1 il- Confi 1 Physical data

Example R Chemical R & D-

36 -CH CH CH Ci E oil 2 2 2

37 Z

38 -C-CH CH Ci E 2 2 & 3

39 H 3

CH 2 CH 2 F E

CH 3

Example 40

  (E) -I- (6-methyl-6-methoxyhe-2-en-4-ynyl) -2- (1-naphthyl)

piperidine oil.

Example 41

  (Z) -1- (6-methyl-6-methoxyhept-2-en-4-ynyl) -2- (1-naphthyl) piperidine, NMR Spectra 13 (CDCl 3 TMS, room temperature, 90.degree. M Hz)

Example

  I (E) 8.2-8.35 (M, 1H); 7.65-7.95 (m, 2H); 7.35-7 (6n, 4H); 6.26 (dt, J = 16 & 2 x 0 595 Pz, 1H), 5.72 (dt, J = 16 2 x, 5Hz, 1H); 3.9 (s, 2H); 3) 36 (s, 3H, 3115 (ddy J = 675 & 115 Hz,

  2H); 2.2- (s, 3H); 154-6 (s, 6 P).

  I (Z) 8.1-8.25 (m, 1H), 7.65-7.8 (m, 2 "); 25-7.5 (m, 4 M); , J = 11 & 2 x 6.5 Hz 1 H), 5.6 (dt, J = 11 Li 2 x Fiz, 1H), 3.84 (Si 2 P 'i; 3 y 3 - (s, 3 -Li); 3.3 (dd, J 6 5 & 1 rice, 2 Li); 2718

(SI 3 P,);

  7.8 (dd, J = 7.5 Hz, 1H); 7.2-7.55 (m, 4 Fn, 6.3 (dt, J = 2 x 6 Hz, 1H), $ 74 (dt, 3 16 & 2 × 15, Fiz, 1). H); 3, P, (SI 2 H); 3.36 (Si 31 H); 3.15 (dd, J 6 & 1.5 Hz, 2 i-1): 2115 (if

3H,%; 1.46 (SI 9H).

  7.8 (dd, 3-7 & 2.5-11, 1H); 2-7,515 (m, 4-H, 692 (dt, JI 2 x 6 Hz-1H), 5.7 (dt, J = 11 & 2 x 1.5H, IP); 3.38 (SI 3 H), 3.36 (dd, J 6 & 1.5 Hz, 2H), 2, 2-, I (s,

3H); 1148 Cs, 6H).

  7.77 (Cl J = 7 & 2 Hz, IPO; 7, I 5-7 (rn, 3H); 6.25 (dt, J 16 & 6.5HZ, 1H); 5.7; (dt, J = 16 & 2 x 'L ,, 5' 14 z, 1H ', 31.76 2 M), 3133 (s, 3H), 3.1 (dd i 6 5 & 1.5 Hz, 2H); ) 2% (SI 3%)

l 44 (SI 6 H).

  1.777 (dd, J = 72-100, 1H); 7.2 -7.5 (mZ% 4 (dt, J11 & 6.5 Hz, 1He; 5, C 5 (dt, -J & -2xl, 5111, 11-i), 3 e 79 (SI 2 H), 3 d, 34 (ss 3 H), 3.3 Icldj i 6.5 & 13 5 Hz, 2 P) i 2> 22 (s,

3H 1 ,; 1.44 (s, 6H).

  BD 2-8; 4 (m, 1H); 7, 7-7395 (, n, 21H); 7,315-7% M, 14H); 24 (dt, J 16 & 2 x 6.5 Hz, 1H); 5.7 (dt, J16 & 2 xl, 5 Hz, 1H); 3 e 8 B (SI 2 H); 3.53 (qua, J = 7 Hz, 2H); 3.14 (dd, J = 6 & 5)

  1.5 Hz, 2 iri); 2.22 (SI 3H); 1.45 (s, 6H); I 8 (t, J 7 Hz, 3 H).

  7 8.2-8.4 2H); 7.7-7.95 (m, 2H); 7e 35-7.6 (m, 4-H); 6) ECI (dt, J = 11 2 x 6.5 Hz, 1H); 5) 67 (dt, J = 11 at 2 x 195 Hz, 1H); 319 (s, 2 P 1; 3, 62 (qua, J = 7Hz, 2H); 3.36 (dd, J = 6.5);

  1.5 Hz, 2H); 2525 (SI 3H); 1, -1-B (s, 6 F-1); 1> 2 (t, J = 7 Hz, 3H).

  7.77 (dd, J 7 & 2 Hz, 1H); 3-7.6 (m, 4H); 6.20 (dt, J 16 & 2 x 6.5 Hz, 1H); 72 ((det, J = 16 & 2 x 1.5 Hz, 1H), 3.78% (S, 21-1), 3.6 (qua, J = 7 Hz, 2H), 3 (dd , J = 6.5 &

  Hz, 2H); 2 e 2,,, 3 H); 1.46 (s, 611); 1.2 (t, J = 7 Pz, 31-i).

  7.76 (dd, J = 7 & 2 Hz, 11-1); 7.2-7.5 (in, 4H); 6.16 (dt, J 9 Il & 2 x 6.5 Hz, 1H); 5 e 66 (dt, J11 & 2 xl, 5 Pz, 1H); 3.78 (s, 2H); 3.6 (qua, J = 7 Hz, 2 F-1); 39 5 (dd, J = 6.5

  1.5 Pz, 2H); 2.26 (t, 31-1); 1.46 (s, 6H); 1; 2 "t, J = 7 Hz, 3HJ.

  8.2-8 (m, 1H), 7.7-7.95 (in, 2H); 7.35-7.6 (m, 4H); 6 3 (dt, J = 16 & 2 x 6 Hz, 1H); 6572 (dm, J = 16Hz, 1H); 3.9 (s, 2H); 3.4 (d, J = 2 Hz, 2H% #; 3.15 (d, J 6 Hz, 2H); 2,, 7 (qua, J

  7 Hz, 2H); 2.24 (s, 3H); ft, J = 7 Hz, 3H).

  8.2-8.4 (m, 1H); 7.65-7.95 cm, 211); 7.35-7.65 (m, 4H); 6 12 (dt, J 11 & 2 x 6 Hz, 1H); 6.66 (dm J 11 Hz, 1H); 3192 (s, 21-1); 3 4 (d, J = 2 Pz, 2H'l; 36 (dd, J 6 & 1 Hz, 2H); 2.7

  (qua, J 7 Hz, 2H); 2; 27 (s, 3H); li 3 (t, J = 7 Hz, 3H).

  8.2-8.4 (in, 1H, 7 65-7, 95m, 2MJ%, 7.4-7.65 (in, -, ', H), 6.3 (dt, J = 16 at 2 x 6 Pz, 1 P) 5.75 (dm, J 16 Hz, 1H) 3.92 (s, H) 3.7 (dm J = 7 Hz, 1H) ; 3.1 B (c 1, - J 6 & 2 x 1, 5 Hz, 2 H) ,;

  2.26 (s, 3H-O, 2, 25 (s, 3H); 1 5-1 (d, J = 7Hz, 3H).

  8.2-8.35 (m, 1H); 7.7-7 to 95 (in, 2H); 7.35-7.65 (in, 4H, 6.38 (dt, J = 16 & 2 x 6Hz, 1H), 5.7 ', (dm, J = 16Hz, 1H), 5.4; (d, Jw1, 5 Hz, 1H); 3 y 9 (s, 2H); 3,4-3,95 'AB part of ABX system 3 JAB = Hz, 4-H); 3.15 (dd, J = 6 & 1.5 Hz, 2H);

  2; 24 3H); 1) (t, J = 7 Hz, 6H).

  14.8 15-8.35 (in, 1H) I; 7.65-7.95 (in, 2 P); 7.3-7.6 (m, 1H); 6.2 (dt, 16, 2 x 6.5 Hz, 1H); 65 (dt, J = 16Co (2x1.5Hz, 1Fe, M6, fs, 2H), 3.1 (dd, J = 6.5, 5Hz, 2H); 2,4-8 (s, 2H) /; 2

(s, 3H); 1.36 (s, 6H).

  812-8) 4 (rr-, 111 '); 7, 65-71.9 (mp, 211 A, 7H (m, 4H), 612 (dt, J = 11 & 2 x 6.5H, 1H), 62 (dt, J); = 2 μl, 5 Pz, 1H), 319 (s, 2H), 3.35 (dd, J = 655 1.5 Hz, 2H), 2.46 (s 2 "),,

252.5%, 31%; I 36 (s, 6H).

  7.65-785 (m, 1H), 7H (M, 4H); 6.24 (dt, J 16 & 2 x 6.5HZ, 1H); 5166 (dt, J = 16 & 2 x 1.5 Hz, 1H), 3.75 (s, 2H); Λ (dd, J = 65 & 1.5 Hz, 2H); 2 e 5 (S, 2H); 2.2 (s, 3H);

36 (s, 6H).

  17 7 65-7.85 IH) I; 1-75 (m, 4H, 5; 16 (dt, J = 11 S 2 x 6 '5 Hz, 1H); 5.6 (dt, J = 11 x 1) 5 Hz', s, 2H); there 1 1 -M); Z 3533 (dd, J = 655 Hz, 2H); 2 e 4 g (s, 2H); 2.25 (s, 3-Li);

1 JS Cs, 6H).

  8.2-8.4 (m, 1H); 7) 7-830% fm, 21H); 7.35-7.6 (m, 4H), 61.3 (dt, J = 16 and 6 Hz, 1H); 6.7 (dt, J = 16.2 x 1.5 Hz, 1H); 3; 9 (s, 2H); 3% (% said, J = 65 & 1.5 Hz, 2H), 2; 2-4 (s, 3H); 1) 74

(t, i = 315 Hz, 3H).

  19 919 (t, J = 3 Hz, 1H); 852-M r 1 m; 1 'A' #; 7; 7-7 p 5 (m, 29-0;

  7 (fr, 4H); 6; 2 (dt, J = 16 & 2 x 6 Pz, IHII; 517 (dt, J = 16 & 7 xi, 5 Pz, 1 H '/; 3 9 (s, 21-); 3.14 (dd, J); = 6 to 2 1.5 Hz,

  2H); 2-4 (d, J = 3 Hz, 2H); 24 (s, 3-Li); Ip (s, 6H).

  8.15-8.35 (m, 1 H; 7 e 65 1; 95 (M, 2H); 7; 3-7 6 (m, 4H); 6.18 (dt, J = 16 & 2 x 6,, 5 Hz, 1H), 5965 (dt, J = 16 & 2 x 1.5 Hz, 1H), 3.9 (s, 2H), 3.84 (t, J = 7 Hz, 2 F-11), 3.12% tdd, J = 6.5 & 1.5 Hz, 2H); 22 (s, 3H); 117 (t, J = 7 Hz, 2H); 1.7 (br, OH);

1124 (s, 6H).

  8112-8.4 (m, 1H); 7.7-7.95 (m, 2H); 35-7.65 (m, 4H); 6; 3 (dt, J = 16 & 2 x 6 Hz, 1H); 5.72 (dm, 36 Hz, 1H): 5.23 (di, J 2 Hz, 1H), 3.88 (s, 2H); 3.15-3.65 (m, 4H); 3, 14 (dd, J = 6 &

* Hz, 2H); 2.22 (s, 3H).

  8.15-8.3 (m, 1H); 7165-7.9 (m, 21H); 7.3-7 6 (m, 4 HJ%; 673 (and, J = 16 & 2 x 6 15 Hz, 1H); 5.8 (from t, J = 16 & 2 xl Hz, 1H);

  3.88 (s, 2H); 14 (dd i = 65 & 1 Hz, 2Hi, 2.2 (s, 3H).

  8.2-8.4 (m, Li); 7-8% (M, 2H); ## EQU1 ## where: J = 16 & 2 × 6.5 Hz, 1H); 5; 7 (dt, J = 16 & 2 × 15 Hz, 1H); ), M (s 2 H); 3 I 4 (dd J = 6.5 & 1, liz, 2H; 2);

  3H); 1; 74 (d, J = 7 Hz, 1H); 1.65 (s, 3 M); 1;, 43 (d, J = 7 Hz, 1H).

  812-814 (m, 1H); 7.7-8.0 (mp, n = 7.4-7.65 (m, 4 F-1); 6; 16 (d = J = 105 & 2 x 6; 5 Hz, 1H); (56 (dt, J = 0, 2 x 115 Hz, 1H); 3, 92 (s, 2 H '; 3138 (dd, J = 6; 5 1; 5 Hz, 2 H'; 2124 (s, 3H), 76 (d, J = 7 Hz, 1H), Ifi (s, 3H), 1, 52 (d, J);

7 Hz, 1 H).

  7178 (dd, J 7 & 2 Hz, 1HJ; 7.2-7.5 (n-, 4, H '); 6e 32 (dt, J 16 & 2 x 6.5 Hz, 1H); 72 (dt, J = 100, 115 Hz, 11.78 (s, 2H), 3) 14dd, J = 65 & 115 Pz, 2 '); ; 2.22 (s, the 76

  (d, J = 7Hz, 1H) 11.58 (s, 31-1); L 46 (d, J 7 Hz, 1H).

  26 7> 76 (dd, J = 7 & 2 Hz, 1H); I-715 (M, 4 P); 6318 (dt, J 1015 & 2 x 6.5 Pz, 1H); 5.65 (Jt, J = 10.5 & 2 x 11.5 H 1 H); 3.80 (s, 2H); 34 (dd, J = 615 & 1.5Hz, 2H) -, 2; 25 (s, 3H); 1 74 (d, J 7 Hz, 1H-1, 1758 (s, 31-INI; 1148 (d, J 7 HZ, 27 7 B (dd, J 7 F 4 2 Hz, 1H); 7142 (ts 3 7 Hz, 7 H 2-7 45 (M, 2 H), O '28 (c 1 t, J = 16 2 x 6 5 Hz, X, 517 (dt, J = 16 2 x 1.5 Hz) , 1H); B (s, 21-i); 3 1 (dd, J = 615 & 1.5Hz, 74 (d, J 7Hz, 1H); L 55 (s, 3H); J; 1146 (d, 2H); 212 (s, 3H);

J = 7 Hz, 1H).

  7178 (dd, J = 7 and 2 Hz, 1H); 7.42 (t, J 7 Hz, 1 Li); 752-7 (m, 2 F-1); 6316 (dt, J = 1 Oe 5 & 2 x 6 5 Hz, 1H); 5.62 (d 1075 & 2 x 1.5 Hz, 11-4); 3178 (at, 2H, 3 Cd, J = 65 Hz, 2H); 72 (d, J 71 Pz, IP); 1155 's, 3H);

1 * 48 (d, J 7 Hz, 1H).

  29 8 2-8 4 1-M); 7- if O2 i-41 ,; 7 35-7.65 fm, 44 "; ke'19 (dt, J 1 6 & 2 x C-5 Mz, 11-l '); 5-YB (dt, J In' 2 x 15 Hz, Ifi 3.9 (s, 2 '-'); 3 55 (I), Fiz, 3,3 '+ (s, 3: -'; 3; 12 (ddy J = 65 & 15 Hz , 2 P, '; 2; 1) 2 (s, -3 H); 17 (t, J 7 H :: 2H);

1.2 (s, 6H).

  8 2-8 4H1); 7.7-8 O 2 H; 7-7.1) 5 (r 6 OER (dit) 2 x 6 5 Hz, 1Hl; 5; 66 (dt, J1015 2 x 1.5 Hz, 1H); 3 92 (s, 2H); ; 3; 6 (t, J = 7 Pz, 2H'J; 34 (dd, J = 615 & 15 Hz, 2H); 43 (s, 3 FA); 2 2 f es, 3H; 1 74 't' J =

7 Hz, 21-1); 1124 (s, 6H).

  6.9-7.17 (m, 3H); 6 22 (dt, J m 16 & 2 x 5 Hz, 1 1-i / '; 5 7 (dt, 16 2 x 1.5 Hz, 1 Fi); 37 5 (s, 31-i; 3.05 (dd, J = 6.5 o ú

  1.5 Pz, 2H); 2, 6-2, 95, 40 '; 2 2 (s, Y 1 ''; 65-

11.05 H), 16 (s, 6H).

  32 6.9-7.3 31-ii; 6.09 (dt, J 11 or 7 x 6.5 Hz, 1H, 5.66 (dt,

  J = 11 2 x 11.5 Hz, 1HJ; 3-4 '(s, 2H); 3.40 (S 'ir); 3.3 (dd, -

  J = 6.51 Pb, 2H; 2.6-2.9 (m, 4H, 2.22 (s, 3H, 1.6-2P)

4H); 1.5 (s, 6H).

  33 8 2-8 4IH); 757-BO 2 P); 714-7.65 (m, 4H); 6) 34 '(dt,

  J = 16 & 2 x 6.5 Hz, 1H); 5177 (ddd, J = 16, 2 & 1, 5 Hz, -

  1H); 4.65 (d, J = 2 Hz, 1H, 3,9 (s, 21-i); 3d (dd, J = 6, 5

1.5 Hz, 2H) -, 22 (s, 9H).

  2-8.4 (m, 1H); 7> 7-810 (m, 2H); 7.3-717 (m, 4H); 6 3 (dt, J 16 and 2 x 6.5 Hz, 1H); 5.76 (dt, J = 0, 2 x 1.5 Hz, 1H); 3.9 (s, 2H), 34 (dd, J = 615 & 115 Hz, 2H); 2.22 (% 9F);

1) 84 (st 3 H).

  8.2-8.4 (m, 1H); 757-BC (m, 2H); 3-7 65 (m, 4H); 6 e 18 (dt, 3 = 10.5 & 2 x 6.5 Hz, 1H); 5175 (dt, J = 10 5 & 2 x 1.5 Hz, 1H); 3, 95 (s, 2H); 34 (dd, J = 6.5 & 1 Hz, 2H);

  2.28 '(s, 3H); 26 (s, 6H); 88 (s, 3H).

  36, 852-854 (m, 1H); 757-8.0 (m, 2H); 74-7.6 (m, 4H); 6; 24 (dt, J = 16 & 2 x 6.5 Hz, 1H); 5.66 (dm, J = 16Hz, 1H); 3.9 (s, 2H); 66 (t, J = 7 Hz, 2H); 3.15 (dd, J = 65 & 1 Hz, 2H);

  2., 5 (tbr, J = 7 Hz, 2H); 2.22 (s, 3H); 2.0 (that, J = 7 Hz, 2H).

  8.2-8.4 (m, 1H); 7.7-8.0 (m, 2H); 7.4-7.65 (m, 4H); 6.1 (dt, j = 10) δ & 635 Hz, 1H); 5566 (dm J = 10.5 Hz, 1H); 3.94 (s, 2H); 68 (t, J = 7 Hz, 2H); 3.38 (dd, J = 6.5 to 1.5 Hz, 2H);

  2.55 (tbr, J = 7 Hz, 2H); IP 26 (s, 3H); 2,, 03 (which, J = 7 Hz, 2 H).

  6.2-8.4 (m, 1H); 7.65-8) 0 (M '2H); 3-7 (m, 4H); J 24 (dt, J = 16 & 2 x 6.5 Hz, 1H); 5.67 (dt, J = 16 & 2 x 1, 5 Hz, 1H); 3.9 (s, 2H); 3.55-3.8 (m, 24); 31.12 (dd, J = 6: 5;

  I., 5 Hz, 2H); 2.22 (s, 3H); 1 8-2.0 2H); 1 24 (s, 6H).

  39 8 2-8 A 1H); 7, 65-80 (m, 2H); 7.3-7.6 (m, 4H); 22 (dt, J = 16 2 x 6.5 Hz, 1H); 5.65 (dm, J = 16Hz, 1H); 45.7 (dt, J = 47 2 x 7 Hz, 2H); 3; 9 (s, 2H); 3.12 (dd, J = 6 and 45 Hz, 2H); 2.2 (s, 3H); 1, 3 (dt, J = 24 2 x 7 Hz, 2H); 1 22 (s, 6H). EI 2-SB (br, IP NJ; 7.2-7.9 Cr-, 6H); 6.1 (clt ', d, J = 16, P, & 6 Hz, 1H); 5.5-1 (e-m, J = 16Hz, 1H ', 3.6-4It (% 3 dy)

in, 1H); 3 36 fs 3 H) -

  1.1-3.4 (m, H), 24-2.7 (m, 1H172-233m, 7-Li); 1144 (s,

6H).

  41 8 4-8 9 (br, 1 H '; 732-7-9, 61-1); 5.96 J = 11.86 Hz-, 11-1; 5, 42% d-n, J = 11 Hz, 1H'i; 3; 6-4 O (m, -1-1-i); 26

  31 i '; 8-3 4 fn-1, 31-11; 112-2, 4 (m, 7-t-1; 1H (s, 61-0.

  s = singlet, d = doublet, t = triplet, qu = quadriplet, m = multiplet,

br = large.

  The starting materials necessary for the preparation of the compounds of the formula I can be prepared for example as follows: A) 1-bromo-6-methoxy-6-methylhept-2-en-4-yne (a) 6-methoxy-6-methylhept- 1-en-4-yl 3-ol

  To 127 ml of a -1.6% solution of n-butyllithium

  thium in hexane is added dropwise under an inert gas atmosphere and at -20.20 g

  of 3-methoxy-3-methyl-1-butynedan in 200 ml of tetrachloride

  anhydrous hydrofuran The solution is cooled to -70 and 11.4 g of acrolein in tetrahydrofuran are added dropwise. The reaction mixture is heated to room temperature, poured into a saturated aqueous solution of ammonium chloride, the extract with ether,

  the organic phase is dried and concentrated.

  By distillation at 58 at 0.2 mbar, we obtain

the pure product in the oily state.

  b) 1-bromo: 6-methoxy-6-methyl-Et-2-ne-4: yne (E / Z mixture)

  12 g of 6-methoxy-6-methylhept-

  1-en-4-yn-3-ol in ether and added

  dropwise at 0-10; 5 g of phosphorus tribromide.

  Stirring is continued for 1 hour and then poured into ice,

  the ether extract and the organic phase is dried.

  The crude product thus obtained no longer contains starting material (thin layer chromatography: 9/1 mixture of toluene and ethyl acetate as eluent, Rf of the product = 0.8, Rf of the starting product = 0, 1) and is used directly as

  This solution is used for N-alkylation.

  By proceeding analogously to that described under Aa) or as previously described, the following compounds can be prepared: 6-ethoxy-5-methylhept-11-en-4-yn-3-ol , 7-6.2 (m, 1 H), 5.0-5.6 (nl, 2H), 4.85 (d, J 4.5 Hz, 1H), 3.7 (br, OH); ) 3.6 (qua, J =: 7

  Hz, 2H); 1.5 (s, 6H); 1.2 (t, J = 7 Hz, 3H).

  6-ethylthiohex-1-en-4-yn-3-ol (oil: thin-layer chromatography: 9/1 toluene mixture

  and ethyl acetate as eluent, Rf = 0.26).

  6-methylthiohept-1-en-4-yn-3-ol (E = 1200

  under 16 mbar in a bulb tube).

  6,6-di-ethoxyhex-1-en-4-yn-3-ol.

  7-cyano-6,6-dimethylhept-11-en-4-yn-3-ol <oil; NMR spectrum: 5.7-6.3 (mi, 1H); 5.0-5.6 (nl, 2H); 4.85 (d, J = 4.5 Hz, 1H); 3.1-3.8 (br, OH); 2.55 (s, 2H);

1.4 (s, 6H).

  6,6-dithioéthylènehex-l-ene-4-yn-3-ol.

  5- (l-methyl-2,2-dichlorocyclopropyl) pent-1-

  ene-4-yn-3-ol (oil, thin layer chromatography: eluted toluene-eluent, Rf = 0.15) 6,6-dimethyl-8-methoxyoct-1-en-4-yn-3-ol . By proceeding in a manner analogous to that described under Ab) or as described above, the following compounds can be prepared 6-ethoxy-1-bromo-6-methylhept-2-en-4-yne 6-ethylthio-11-bromohex -2-en-4-yne 1-bromo-6-methylthiohept-2-en-4-yne 1-bromo-6,6-diethoxyhex-2-en-4-yne 1-bromo-7-cyano-6,6- methyl-hept-2-en-4-yl-1-bromo-6-di-thioethylenhex-2-en-4-yl-bromo-5-iodopent-2-en-4-yne

  1-bromo-5- (1-methyl-2,2-dichlorocyclopropyl) pent-2-

  ene-4-yne, and 1-bromo-6,6-dimethyl-8-methoxyoct-2-ene-4-yne. B) 1-Bromo-7,7-difluoro-6-methylhepta-2,6-dien-4-yne a) 1-tert-butyldimethylsilyloxy-4-pentyne-2-ene To a solution of 5 g of 4-pentyne-2 -ene-l-ol

  and 9.3 ml of triethylamine in dimethylformate

  mamide, add drop by drop to the temperature

  10.1 g of tert-butyldimethylchloride

  silane Stirring is continued for 1 hour, the mixture is poured into ice and

  the extract with hexane The washing phase is washed

  dried, and concentrated. The oily crude product thus obtained is used

  directly for the next reaction.

  b) 1-tert-butyldimethylsilyloxy-6-hydroxyhept-2-

ene: l: YNT

  10.7% of 1-tert-butyldimethyl

  silyloxy-4-pentyne-2-ene in anhydrous tetrahydrofuran-and dropwise at -50, 44 ml of a 1.6 M solution of n-butyllithium

  in hexane and then at -70.4 ml of acetal-

  dehyde The cooling bath is removed and

  The mixture is then poured overnight at room temperature. The mixture is then poured into ice, extracted with ether and the usual after-treatment is carried out. The oily crude product thus obtained is chromatographed on silica gel using as eluent, a 95/5 mixture of toluene and ethyl acetate is obtained

  thus 1-tert-butyldimethylsilyloxy-6-hydroxy-

  hept-2-ene-4-yne as a colorless oil.

  NMR spectrum: 6.2 (dt, J = 16 and 2 x 3.5 Hz, 1H); , 75 (dm, J = 16 Hz, 1H); 4.5 - 4.8 (m, 1H); 4.2 (dd, J = 3.54, 2 Hz, 2H); 1.8 (d, J = 5.5 Hz, OH);

  1.45 (d, J = 7 Hz, 3H); 0.9 (s, 9H); 0.05 (s 6H).

  c) I: tert-butyldimethylsilyloxyhept-2-ene-4-yne

  6-one Shake overnight at room temperature

  ambient, a mixture of 6 g of 1-tert-butyl-

  dimethylsilyloxy-6-hydroxyhept-2-ene-4-yne and 21% MnO 2 in dichloromethane, then the mixture is filtered and concentrated. The product thus obtained in the form of an oil is used.

directly for the next step.

  IR spectrum: 1665 cm 1 (C = O), 2180 cm 1 (C-C) NMR spectrum: 6.6 (dt, J = 16 and 2 x 3.5 Hz, 1H); , 95 (dt, J = 16 and 2 x 2 Hz, 1H); 4.3 (dd, J = 3.5 and 2 Hz, 2H);

  2.4 (s, 3H); 0.95 (s, 9H); 0.1 (s, 6H).

  d) l-tert: butyldimethylsilyl 2 xy: 7,7-difluoro-6-

Methy 1 hejta-2,6-diene-4-yne

  To a solution of 1 g of 1-tert-butyl-dimethyl

  silyloxyhept-2-en-4-yn-6-one and 0.77 ml of dibromofluoromethane in anhydrous dimethylacetamide, a solution of 1.52 ml of tris (dimethylamino) phosphine in dimethylacetamide is added dropwise at 0.degree. Stirring is continued for 1.5 hours at room temperature and 0.55 g of zinc powder is added. The mixture is stirred at 100 for 1 hour, filtered, poured into ice and dried. Extracted with hexane The organic phase is washed with saturated aqueous sodium chloride solution, dried and concentrated. The residue is chromatographed on silica gel using a 100: 5 hexane mixture as eluent. and ethyl acetate The title compound is thus obtained

in the form of a colorless oil.

  IR spectrum: 1720 cm -1 NMR spectrum: 6.22 (dt, J = 16 and 3.5 Hz, 1H); 5.85 (dm, J = 16Hz, 1H); 4.24 (dd, J = 3.5 and 2 Hz, 2H); 1.73 (t, J = -3 Hz,

3H); 0.9 (s, 9H); 0.06 (s, 6H).

  e) 1-bromo-7,7-difluoro-6-methylhelta-2,6-diene-4-: yne

  3 g of 1-tert-butyldimethylsilyl are dissolved

  oxy-7,7-difluoro-6-methylhepta-2,6-di-4-yne in tetrahydrofuran and added to O

  16.5 ml of a 1 M solution of tetrahydrofluoride

  butylammonium in tetrahydrofuran After

  one half hour, the reaction is over (chromatic

  thin layer graph: toluene as eluent,

  Rf = 0.1 compared to Rf = 0.9 of the starting material).

  The mixture is poured into ice and extracted several times with ether. The organic phase is washed with saturated aqueous sodium chloride solution and dried.

  the concentrate is dissolved 7,7-difluoro-6-methyl-

  hepta-2,6-diene-4-yn-1-ol thus obtained in ether and added dropwise to O

  0.5 ml solution of phosphorus tribromide in ether.

  The reaction is complete after half an hour (thin-layer chromatography: toluene as eluent, Rf = 0.9 compared to Rf = 0.1 of the starting material). The mixture is poured into ice, the ethereal phase is isolated. we wash it and we

  The ethereal solution of 1-bromo-7,7-difluoro-

  6-methylhepta-2,6-dien-4-yne thus obtained is

  used directly for subsequent alkylation.

  C) 3-methylthio-1-butyne To 15 g of 3-methylthio-1-propyn in anhydrous tetrahydrofuran was added dropwise to -40 113 ml of a 1.6 M 1 solution of n-butyllithium

  in hexane and then at -70.23 ml of trimethyl-

  Chlorosilane The cooling bath is removed, the reaction mixture is heated to room temperature and poured onto ice.

  the mixture with ether, the organic phase is dried

  and concentrates it 3-methylthio-1-

  Trimethylsilyl-1-propyn crude thus obtained is dissolved; in anhydrous tetrahydrofuran; It is reacted at -70 with 80 ml of a 1.6 M solution of n-butyllithium in hexane and 8.7 ml of methyl iodide are added dropwise. The cooling bath is removed and dried for one hour. later, the mixture is poured onto ice. The mixture is extracted

  with ether, the organic phase is washed with a solution of

  aqueous solution of sodium bicarbonate, dried and concentrated by distillation at 70 ° C.

  9 m bar in a bulb tube, 3-methyl-

  Thio-1-trimethylsilyl-1-butyne in the form of an oil This oil is stirred for 45 minutes at room temperature in a solution of 3.3 g of sodium hydroxide in methanol and then partitioned between pentane and a saturated solution of sodium chloride The organic phase is washed,

  it is dried and the pentane is distilled off

  column pressure at normal pressure By distillation

  at 98-102, we obtain the title compound

in the form of a colorless oil.

  D) N- (7-benzolblthienylmethyl) methylamine a) 7-bromomethylbenzolblthiophene 7 g of refluxing are heated for 6 hours

  of 7-methylbenzolblthiophene with 8.5 g of N-

  bromosuccinimide and a spatula tip of a, a'-

  azoisobutyronitrile in 50 ml of carbon tetrachloride The mixture is then cooled,

  filtered and concentrated 7-bromomethyl-

  The crude benzolblthiophene thus obtained can be used directly in the next step. b) N: 7 benzolblthienylmethyl), ethylamine 7-bromomethylbenzo [b] thiophene is dissolved in dichloromethane, the stirring solution is added to 40 ml of a 33% ethanol solution of methylamine and allowed to stand overnight The mixture is concentrated The residue is taken up in dichloromethane and extracted with 2N hydrochloric acid. The aqueous phase is made alkaline with hydroxide.

  of sodium and stirred with dichloromethane.

  The organic phase is dried over potassium carbonate, concentrated and the residue is distilled off in vacuo to give the title compound as a boiling oil at 1030 ° C.

1.3 m bar.

  E) N- (3-chloro-7-benzol-1-thienylmethyl) methylamine a) 2,3-dichloro-7-methylbenzo-1-thiothene 20 g of 7-methylbenzolblthiopene are dissolved in carbon tetrachloride and saturated at room temperature with chlorine After

  2 hours, the excess chlorine is removed,

  The mixture is washed and the residue is taken up in dichloromethane. The organic phase is washed with a saturated aqueous solution of bicarbonate.

  of sodium, dried and concentrated.

  After recrystallization from methanol, the title compound is obtained in the form of crystals

colorless melting at 45-47.

  b) 3: chllro 7 Zmethylbenzolblthioehene

  10 g of 2,3-dichloro-7-methyl-

  benzoethiophene in 200 ml of ether and

  added dropwise to 28.8 ml of a solution

  1.6 M n-butyllithium in hexane. After about 1 hour, the mixture is poured into a dilute aqueous solution of hydrochloric acid, the organic phase is separated off, washed, dried and concentrated by distillation in vacuo to give the title compound of the title compound. pure state, in the form of an oil E = 60-62 /

0.13 m bar.

  c) N-: 3: chloro-7-benzo-E-thienylmethyl-2-methylamine The product is obtained by proceeding in a manner analogous to that described under D) E = 130132 / 1.3 m bar (the hydrochloride

at 250-255).

  NMR spectrum: 7.78 (dd, J = 7 and 2.5 Hz, 1H); 7.25-7.55 (m, 3H); 4.05 (s, 2H);

2.45 (s, 3H); 184 (s, NH).

  F) 3,3, -diiethyl-5-methoxy-1-pentyne a) 3, 3: imethyldi-2-tyne-5-ol 6 g of 3,3-dimethyl-1-pentyne- 5-al

  in ethanol and reacted under stirring.

  With 1.3 g of sodium borohydride After stirring for a further 2 hours, the solvent is distilled off and the residue is partitioned between ether.

  and an aqueous solution of sodium chloride.

  The organic phase is dried and concentrated under normal pressure. After distillation in a Kugelrohr tube, the title compound is obtained in the form of a colorless oil. B) 3,3-Dimethyl-5-methoxy-1-pentyne A A suspension of 3.5 g of NaH (80%) in tetrahydrofuran is added dropwise to O 7 g of 3,3-dimethyl-1-pentyne-5-ol and after 30 minutes of stirring. Dimethyl sulfate is slowly added. The cooling bath is removed and stirring is continued at room temperature for 3 hours. The excess NaH is destroyed with glacial acetic acid and the solvent is evaporated off. under normal pressure The residue is partitioned between water and hexane, the organic phase is washed, dried and

  Concentrate under normal pressure

  tion-to 113-115 in a tube to balls, we get

  the title compound as an inconsistent oil

  lore. G) 1-Bromo-6,6-dimethylthiohex-2-ene-4-yne a) 1-tert butyldiethyl-phenyloxy-2-ene-4-yne The procedure is as described under (B).

  the title compound as an oil.

  NMR spectrum: 7.3-7.8 (m, 1H); 6.34 (dt, J = 16 and 2x4 Hz, 1H); 5.9 (dm, J = 16Hz, 1H);

  4.24 (m, 2H); 2.9 (m, 1H); 1.04 (s, 9H).

  b) 1-tert-butyl-diphenylsilyloxy-6-hydroxyhex-2-ene

  4-yne We proceed as described under Bb) We get

  thus the title compound as an oil.

  NMR spectrum: 7.3-7.8 (m, 10H); 6.24 (dt, J = 16 and 2x4 Hz, 1H); 5.9 (dm, J = 16Hz, 1H); 4.4 (dbr, 2H); 4.25 (m, 2H); 1.7

(t, J = 7 Hz, 1H); 1.04 (s, 9H).

  c) 1-tert-butyldiphenylsilyloxyhex-2-en-4-yne-6-al The procedure is carried out as described under Bc). The title compound is obtained in the form of melting crystals.

at 51-59.

  NMR spectrum: 9.35 (d, J = 1.5 Hz, 1H); 7.3-7.8 (m, 10 Hz); 6.62 (dt, J = 16 and 2x4 Hz, 1H); 6.18 (dm, J = 16 Hz,

1H); 4.34 (m, 2H); 1.06 (s, 9H).

  d) 1-tert-butyldienylsilyloxy-6,6-dimethylthio-hex-2-ene-4

  To a mixture of 2 g of 1-tert-butyldiphenyl-

  silyloxy-2-en-4-yne-6-al and 170 mg of Zn I 2 in anhydrous ether, 2.4 ml is added dropwise.

  of S (trimethylsilyl) methanethiol and the mixture is stirred

  overnight at room temperature The mixture is then poured into water, washed with

  ether phase, dried and evaporated.

  oily crude oil thus obtained is used directly

in the next step.

  NMR spectrum: 7.3-7.8 (m, 1H); 6.26 (dt, J = 16 and 2x4 Hz, 1H); 5.98 (dm, J = 16Hz, 1H); 4.66 (m, 1H); 4.24 (m, 2H);

2.26 (s, 6H); 1.06 (s, 9H).

  e) 1: bromo-6,6-dimethylthiohex-2-ene-4-yne The procedure is as described under Be)

  thus the title compound as an oil.

  NMR spectrum: 6.35 (dt, J = 16 and 2 x 5 Hz, 1H); 84 (ddd, J = 16.5 and 2 Hz, 1H); 4.67 (d, J = 2 Hz, 1H); 4.24 (dd, J = 5 and 2 Hz, 2H); 2.24 (s, 6H);

1.82 (s, 1H).

  H) 1-bromo-6,6-dimethylthiohept-2-en-4-yne a) 1 trmts 1 btnei 3: The procedure is carried out as described under Bb). The title compound is thus obtained in the form of an oil.

  boiling at 100-101 under 85 m bar.

b) I: Irimethylsilyl-1-u: tyne-1-one

  We proceed as described under Bc) We ob-

  holds the title compound as an oil.

  NMR spectrum: 2.24 (s, 3H); 0.23 (s, 9H).

  c) 1: trimethylsilyl: 3,3: dimethylthio-i-buty

  We proceed as described under Gd) We ob-

  holds the title compound as an oil.

  NMR spectrum: 2.3 (s, 6H); 1.9 (s, 3H); 0.3 (s, 9H).

d) 3,3-dimethylthio-i-butyl

  Stirring is carried out for 1/2 hour at 0 g of

  trimethylsilyl-3,3-dimethylthio-1-butyne in

  a solution of 180 mg of NaOH in methanol.

  After addition of a saturated aqueous solution

  sodium chloride, extracted with

  tane, the organic phase is dried over sulfate

  sodium and carefully remove the soil

  by distillation on a Vigreux column.

  The oily crude product thus obtained is used

directly in the next step.

  NMR spectrum: 2.65 (s, 1H); 2.2 (s, 6H);

1.8 (s, 3H).

  e) 6,6-dimethylthiohe-1-en-4-yn-3-ol

  The procedure is analogous to that described

  under Aa) We get the title compound

in the form of an oil.

  NMR spectrum: 5.7-6.0 (m H); 4.9-5.6 (m, 3H);

  2.2 (s, 6H); 1.9 (s, 3H); 1.5 (O-H).

  f) 1: bromo-6,6-dimethylthioheet-2-ene-4-: ne

We proceed as described under Ab).

  1) 1-bromo-8-chloroct-2-ene-4-yne a) _bu_i_ ___ St

  We proceed as described under Ba) We ob-

  holds the title compound as an oil.

  NMR spectrum: 5.76-6.1 (m, 1H); 5.06-5.55 (min, 2H); 4.8-5.0 (m, 1H); 2.48 (d, J = 2 Hz, 1H); 0.9 (s, 9H); 0.1 (s, 6H).

  b) 3: tert -: butldimethylsil 12 oy-:: -h-loroct-1-ene

4 do not

  2 g of 3-tert-butyldimethylsilylol are dissolved

  xypent-1-ene-4-yr in a 10: 1 mixture of tetra-

  hydrofuran and hexamethyl-phosphotriamide and

  6.2 ml of a solution is added dropwise to

  1.6 M n-butyllithium in hexane.

  0.98 ml of 1-bromo-3-chloropropyl is then added.

  The mixture is then stirred overnight at room temperature. The mixture is then poured into aqueous sodium chloride solution, extracted with pentane and dried.

  organic phase and concentrated on

  the residue on silica gel (eluent:

  98/2 hexane and ethyl acetate) and

  isolates the title compound as an oil.

NMR spectrum: 5.7-6.1 (m, 1H); 4.8-5.5 (m, 3H); 3.6 (t, J = 7 Hz, 2H); 2.5 (t, 2H);

  2.1 (m, 2H); 0.9 (s, 9H); 0.1 (s, 6H).

  c): ct 12 roct-l-ene-4-yq 2: 2: ol We proceed as described under Be) We obtain

  the title compound as an oil.

  Rf (eluent: 4/1 mixture of toluene and acetate

of ethyl) = 0.35.

d) 1-Brono-8-chloroct-2-ene-4-Yn

We proceed as described under Ab).

  J) 1-Bromo-8-chloro-6,6-dimethyl-2-en-4-yne a) _ _ u _ _ _

  3 g of 3,3-dimethylpent-1-yne are dissolved

  and 2.7 g of triethylamine in dichloromethane are added dropwise to 0.1 g of p-toluenesulfonyl chloride. Stirring is continued for 3 hours at room temperature and the mixture is poured into the mixture. in ice-cold 0.1 N aqueous hydrochloric acid. The organic phase is washed neutral, dried and concentrated.

  The raw product thus obtained can be used

  in the next step or chromatogra-

  on silica gel (eluent: toluene).

  NMR spectrum: 7.8-7.95 (m, 2H); 7.25-7.5 (m, 2H); 4.28 (t, J = 7 Hz, 2H); 2.45 (s, 3H); 2.06 (s, 1H);

  1.8 (t, J = 7 Hz, 2H); 1.2 (s, 6H).

b) 5-chloro-3,3-dimethylet: -1

  In the absence of moisture, stirring at 50

  at night 2 g of 3,3-dimethyl-5- (p-toluenesulphon)

  fonyloxy) pent-1-yne with 1 g of LiCl in di-

  methylformamide The reaction mixture is distilled

  nel; the product obtained between 115 and 130 is used

  directly in the next step.

  NMR spectrum: 3.55-3.8 (m, 2H); 2.1 (s, 1H);

1.8 -2.0 (m, 2H); 1.2 (s, 6H).

  c) 8-chloro-6,6-dimethyloct-1: -ene-4-yn-3-o 121 The procedure is as described under Aa)

  the title compound as an oil.

  d) 1-bromo-8-chloro-6,6-dimethyl: α-2-ene: 4-:

  We proceed as described under Ab).

  The title is obtained in the form of an oil.

  K) 1-Bromo-6,6-dimethyl-8-fluorooct-2-ene-4-yl a) 3,3-dimethyl-5-fluorine: ne

  During the night at reflux a mixture of

  266 mg of 3,3-dimethyl-5- (p-toluene)

  sulfonyloxy) pent-1-yne, 5 ml of 1 N tetrabutylammonium fluoride in tetrahydrofuran

  and 2 ml of acetonitrile.

  reaction with water and extracted

  repeatedly with diethyl ether

  that the organic phase is washed, dried and

  the solvent is distilled off under pressure.

  The gross product thus obtained is

  used directly in the next step.

  NMR spectrum: 4.70 (dt, J = 47 and 2 x 7 Hz, 2H); 2.05 (s, 1H); 1.8 (dt, J = 24 and

2 x 7 Hz, 2H); 1.2 (s, 6H).

  b) 6,6-dimethyl-8-fluorooct-1-ene-4-lyne-3-ol

  We proceed as described under Aa) We ob-

  holds the title compound as an oil.

  c) 1: bromo-6,6-dimethyl-8-fluorooct-2-en-4-yne

  We proceed as described under Ab) We ob-

  holds the title compound as an oil.

Claims (10)

  1. Compounds of formula I R, "4 R 2 C -N CH 2 CH = CH C C R 8 (I) R 3   in which a) R 1 represents a group of formula I Ia, I Ib or I Ic -R 6 (CH> R 6   In which R 5 and R 6 each independently represent hydrogen,   trifluoromethyl, lower alkyl or lower alkoxy laughing, s means 3, 4 or 5 and -   X represents -O-, -S-, -CH 2-, -OCH 2-, -SCH 2 or -N (R 7) o R 7 signifies hydrogen or a lower alkyl group, and Rd represents hydrogen or a lower alkyl group, or   R 1 and R 2 represent, with the carbon atom   to which they are attached, a group-of formula I Id (C Hi 2) p- (-.g (lid) in which p is 1, 2 or 3, R 3 and R 4 each independently represent one of the other, hydrogen or a lower alkyl group and   R 8 represents a halogen, an acetal or thio-   acetal optionally substituted with lower alkyl, a halo-alkenyl group, a   halogenocycloalkyl, a lower alkyl group   cycloalkyl, or an alkyl group substituted by lower alkoxy,   lower alkylthio, lower haloalkyl, aceto   tal, thioacetal, cyano, formyl or hydroxy, the carbon atom in a of the triple bond must not have a hydroxy group, or b) R 3 and R together form a group - (CH 2) u or u 3 4   means 3, 4 or 5, R 1 represents a group of formula I Ia, Ib or Ic, R 2 represents hydrogen or a lower alkyl group and R 5 to R 8 have the meanings given above, 2. A compound according to claim 1,   characterized in that R 1 represents a group of mule l Ia.   3. A compound according to claim 1,   characterized in that R 1 represents a group of mule I Ib.   4 A compound according to any one of   Claims 1 to 3, characterized in that R 2 and R 3   represent hydrogen and R 4 represents a group lower alkyl.   5. (E) -N- (1-Naphthylmethyl) -N-methyl-   6-ethoxy-6-methyl-1-hept-2-ene-4-ynylamine.   6. A compound according to any of   Claims 1 to 5, characterized in that it   in the free base state or in the form of a salt acid addition.   7. A process for the preparation of the compounds specified in claim 1, characterized in that a compound of formula III is reacted -R 2 C NH R 4 (III) R 3 with a compound of formula A CH 2 CH = CH C C -R 8   in which a functional group optionally is in protected form,   formulas in which R 1 to R 4 and R 8 have the meanings   cations given in claim 1, and A represents an eliminable group and, if necessary, eliminates any protecting group that may be present and the compound of formula I thus obtained is recovered in the free base state or in the form of a acid addition salt. 8. Use of the compounds of formula I specified in claim 1, in the free base state or in the form of an acceptable acid addition salt   from the chemotherapeutic point of view, as drugs.   9. Use of the compounds of formula I specified in claim 1, in the free base state or in the form of an acceptable acid addition salt   from the chemotherapeutic point of view, as   therapeutic and especially as anti-mycotics.   10. A medicament, characterized in that it contains, as active ingredient, a compound according to claim 1, in the free base state or in the form of an acid addition salt which is chemotherapeutic view.   He. A pharmaceutical composition,   in that it contains a compound according to the   in the free base state or in the form of an acid addition salt which is acceptable from the point of   chemotherapeutic view, in association with a di-   luent or chemically acceptable vehicle. therapeutic.