GB2120663A - Allylamine derivatives, processes for their preparation and their use - Google Patents

Allylamine derivatives, processes for their preparation and their use Download PDF

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GB2120663A
GB2120663A GB08312160A GB8312160A GB2120663A GB 2120663 A GB2120663 A GB 2120663A GB 08312160 A GB08312160 A GB 08312160A GB 8312160 A GB8312160 A GB 8312160A GB 2120663 A GB2120663 A GB 2120663A
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lower alkyl
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Anton Stutz
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Sandoz AG
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Abstract

Compounds of formula I <IMAGE> wherein a) R1 represents a group of formula <IMAGE> wherein R5 and R6 represent independently hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, s stands for 3, 4 or 5 and x represents oxygen, sulphur, -CH2-, OCH2-, -SCH2-, or -N(R7)- (R7=hydrogen or lower alkyl) and R2 represents hydrogen or lower alkyl or R1 and R2 together with the adjacent carbon atom represent a group of formula <IMAGE> wherein p is 1, 2 or 3, R3 and R4 represent independently hydrogen or lower alkyl and R8 represents halogen, acetal or thioacetal, each optionally lower alkyl, substituted halogen alkenyl, halogen cycloalkyl, lower alkylcycloalkyl, or alkyl which is substituted by lower alkoxy, lower alkylthio, lower halogenalkyl, acetal, thioacetal, cyano, formyl or hydroxy whereby hydroxy if present is other than ??? to the triple bond or b) R3 and R4 together form a -(CH2)u- group wherein u stands for 3, 4 or 5, R1 represents a group of formula IIa, IIb or IIc, R2 represents hydrogen or lower alkyl and R5 to R8 have the meanings given above, in the free base or in acid addition salt form. The compounds possess anti-mycotic activity.

Description

SPECIFICATION Allylamine derivatives, processes for their preparation and their use The present invention concerns allylamine derivatives, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals particularly as antimycotics.
More particularly the invention concerns compounds of formula I
wherein a) R, represents a group of formula
wherein Rs and R6 represent independently hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, s stands for 3, 4 or 5 and x represents oxygen, sulphur, -CH2-, -OCH2-, -SCH2-, or -N(R7)- (R7=hydrogen or lower alkyl) and R2 represents hydrogen or lower alkyl or R, and R2 together with the adjacent carbon atom represent a group of formula
wherein pis 1,2or3, R3 and R4 represent independently hydrogen or lower alkyl and R8 represents halogen, acetal or thioacetal, each optionally lower alkyl substituted, halogen alkenyl, halogen cycloalkyl, lower alkylcycloalkyl, or alkyl which is substituted by lower alkoxy, lower alkylthio, lower halogenalkyl, acetal, thioacetal, cyano, formyl or hydroxy whereby hydroxy if present is other than a to the triple bond or b) R3 and R4 together form a (CH2)u group wherein u stands for 3,4 or 5, R1 represents a group of formula Ia, llb or llc, R2 represents hydrogen or lower alkyl and R5 to R8 have the meanings given above, in free base or in acid addition salt form.
The compounds of formula I may be obtained by reacting a compound of formula Ill
with a compound of formula A-CH2-CH=CH-C=-C-R8 in which any functional groups are protected, wherein P1, R2, R3, R4 and R8 are as defined above and A represents a ieaving group and if required then removing any protecting groups present.
The process can be carried out in conventional manner, for example in a solvent, inert under the reaction conditions, such as a lower alcohol, e.g. ethanol, optionally in mixture with water; an aromatic hydrocarbon such as benzene or toluene; a cyclic ether, such as dioxane; or a carboxylic acid dialkylamide such as dimethylformamide and at reaction temperatures of between room temperature (which is preferred) and the boiling point of the reaction mixture. Leaving group A can be for example be halogen e.g. chlorine or bromine or an organic sulphonyloxy group having 1 to 10 carbon atoms, e.g.
alkarylsulphonyloxy such as tosyloxy or alkylsulphonyloxy such as mesyloxy. The reaction is conveniently carried out, when appropriate, in the presence of an acid binding agent e.g. an alkali carbonate such as sodium or potassium carbonate. Where appropriate, functional groups, if present in the starting materials, may be protected by suitable protecting groups which may be removed subsequent to the reaction in conventional manner.
End products can be isolated and purified according to known methods.
The compounds of formula I may be recovered in free base or acid addition salt form in conventional manner. Free base forms can be converted in conventional manner into salt forms and vice versa.
The compounds of formula I and their intermediates can be obtained in the form of mixtures of the various cis/trans isomers which can be separated according to established methods.
Unless otherwise stated alkyl moieties preferably are straight or branched chains having 1 to 1 2 especially 1 to 8 carbon atoms, particularly 1 to 6 and especially 1 to 4. A particular group of such alkyl radicals has 2 or more carbon atoms. Lower alkyl present as or in a substituent is straight or branchedchain and has preferably 1 to 4 especially 1 or 2 carbon atoms. Alkenyl has preferably 3 to 6 especially 3 or 4 carbon atoms e.g. allyl, propenyl. Cycloalkyl is preferably cyclohexyl, cyclopentyl, or cyclopropyl.
Acetals and thioacetals contain preferably 1 to 4, especially 1 or 2 carbon atoms in their respective alkyl moieties or may alternatively be cyclic.
The starting materials of formula Ill are in part new and can be prepared by reacting a compound of formula V
with a compound of formula VI R4NH2 VI wherein R1, R2, R3, R4 are as defined above.
The starting materials of formula IV are in part new and can be prepared e.g. according to the following reaction scheme
whereby, R8 and A are as defined above and Me represents a metal cation.
Reaction conditions are those conventionally employed in such reactions whereby the various intermediates can, where appropriate, be reacted further without isolation. Where isolation takes place it is carried out in conventional manner.
The remaining starting materials and intermediate compounds are either known or can be prepared according to known methods.
The compounds of formula I exhibit chemotherapeutic activity. In particular, they exhibit antimycotic activity, as indicated in vitro in various families and types of mycetes, including Trichophyton spp., Aspergillus spp., Microsporum spp., Sporotrix schenkii and Candida spp., at concentrations of, for example 0.003 to 50 ,ug/ml, and in vivo in the experimental skin mycosis model in guinea pigs. The test substance is administered daily for 7 days beginning 24 hours after the infection either on local application by rubbing the test substance (taken up in polyethylene glycol) on the skin surface or perorally.
The Candida activity (which is especially present in compounds wherein R1=llb) is shown in vivo employing conventional intravaginal/intrauterine- or disseminated-infection models on mice or rats.
The activity is shown on local application at concentrations of for example 0.01 to 0.2%. The oral activity is shown in vivo in the guinea-pig-trichophytosis at dosages of, for example, 2 to 70 mg/kg.
The compounds are therefore indicated for use as antimycotic agents. For this use a suitable total daily dosage is from about 70 to 2000 mg and dosage forms suitably given two to four times daily at dosages of about 1 7.5 to 1000 mg or in retard form.
The compounds may be used in free base form or in the form of chemotherapeutically acceptable acid addition salts. Such salt forms exhibit the same order of activity as the free base forms. Suitable such salt forms are e.g. hydrochloride, hydrogen fumarate or naphthaíine-1 ,5-disulphonate.
The invention therefore also concerns a method of treating diseases or infections caused by mycetes which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I or a chemotherapeutically acceptable acid addition salt thereof as well as compounds of formula I or chemotherapeutically acceptable acid addition salts thereof for use as chemotherapeutic agents especially as anti-mycotics.
The compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and, optionally, other excipients and administered e.g. orally in such forms as tablets or capsules. The compounds may alternatively be administered topically (in such conventional forms as ointments or creams), parenterally or intravenously. The concentrations of the active substance will, of course, vary depending on the compound employed, the treatment desired and the nature of the form etc. In general, however, satisfactory results are obtained e.g. in topical application forms at concentrations of from 0.05 to 5, in particular 0.1 to 1 wt.%.
Such compositions also form part of the invention.
Preferred meanings for the substituents are as follows: R1=a) Ila b) llb R2, R3=H P4=lower alkyl especially methyl R,, R6=a) hydrogen b) halogen especially chlorine R8=a) lower alkyl substituted by alkoxy or alkylthio b) acetal or thioacetal (optionally lower alkyl substituted) as well as combinations of these.
Compounds in which the double bond adjacent to the nitrogen has the trans(E) configuration are preferred.
A particularly preferred single compound is (E)-N-(1-naphthylmethyl)-N-methy-6-ethoxy-6methyl-hept-2-en-4-ynamine.
The following examples illustrate the invention whereby temperatures are given in degrees centrigrade.
Example 1 (E)- and (Z)-N-Methyl-N-(l -naphthyl methyl)-6-methoxy-6-methylhept-2-en-4-yn-amine To a mixture of 16.1 g of N-methyl-(1-naphthyl)methanamine 16.5 g Na2CO3 and 100 ml of dimethylformamde is added dropwise to a solution of 16.9 g 1-bromo-6-methoxy-6-methylhept-2-en- 4-yne (E/Z mixture) in either. After stirring overnight the reaction mixture is filtered and the solvent removed under vacuum. The residue is partitioned between saturated aqueous NaHCO3 and dichloromethane and the organic phase dried, concentrated and chromatographed over silica gel (eluant: toluene/ethylacetate 4:1) to yield first the (E) and then the (Z) isomer as oiis.
The following compounds of formula I may be obtained analogously or as otherwise hereinbefore described.
(R2 = R3 = R - CH3)
Example R, Conf. Phys-chem. R1 e R1 R8 - Conf . data 2=CT CH, Cl ------- - ~9|~ 5 ~|~ ~ it~ Z -" CsH3 -C-0CHH3 E E L (R2 = R3 = H; R4 = CH3)
Example R1 R8 Conf. Phys,-chem. data 7 Oi "' 7 can3 C-OCH2CH3 Z oil CH3 8 ,9 -Ia- E m.p.l54-1560 (hydrochloride) 9 -a'- 11 oil 10 -CH2-S-CH2CH3 E ~ n~ 11 ~11~ ~11~ U Z 11 z CH3 12 ,s~ H-S-CH3 E ~II~ 1 / OC2Hg 13 ~"~ -CH OC2H5 ~n~ OC2Hg 14 ~11~ -C-CH2CN E (hydrochloride) a yroco?e CH3 15 ( ~||~ Z C Z oil 16 It -C- E -'I 17 11 II Z 11 (R2 = R3 = H;R4 = CH3)
Example R1 R8 %cony. Phys.-chem. data 8 X ~W3 E oil CIH3 19 -- can3 E E -C-CH2-CHO CH3 20 ------ Can3 E ~ | CH CH2 CH20H CH3 21 -a' -CH , 2 E ~ "~ \ ,Cn2 22 ~w~ I I E m.p. 145-1480 h drochloride 23 X C113 -c cI/IH2 E (hydrochl ori de ) i C12 24 ,n~ . I Z oil 25 1 -"- E m.p.130-135" (hydrochi or de) 26 26 ~1l -Z Hz .oil , .
27 0 ~ w E -a' (R2 = R3 = H; R4 = CH3)
Example R1 R8 E Phys .-chem. dat 28 Cf,~ 1 I -c: CZl.
W -G CH2CHzOCH3 E 30 ~a~ ~g~ ~ 4 Z a.
31 n can3 I -C-ocn E cn3 32 ~u~ ~a~ C Z 33 SCH 33 3 E \SCH3 34 - "- sCH3 3 E -CH-CH7 35 1 Z - a.
36 ~sue~ -cH2CH2C}I2CI E LLL 37 U - Z CH3 38 -a.- -C-cn 38 ~||~ E 39 -a.- CH3 -C-cn2CH2F E . CH3 Example 40 (E)-l -(6-Methyl-6-methoxyhept-2-en-4-yn-1 -yl)-2-(1 -naphthyl)-piperidine Oil.
Example 41 (Z)-1 -(6-Methyl-6-methoxyhapt-2-en-4-yn-1 -yl)-2-( 1 -naphthyl)-piperidine Oil.
NMR-spectra (CDCl3, TMS, RT, 90 MHz) Example 1(E) 8.2-8.35 (m,1H); 7.65-7.95 (m,2H); 7.35-7.6 (m,4H); 6.26 (dt,J=16 and 2x6.5 Hz, 1H); 5.72(dt, J=16 and 2x1.5 Hz, 1H);3.9 (s,2H);3.36(s,3H); 3.15 (dd, J=6.5 and 1.5 Hz, 2H); 2.24 (s, 3H); 1.46 (s, 6H).
1(Z) 8.1-8.25(m,1H); 7.65-7.8(m,2H); 7.25-7.5 (m,4H); 6.04 (dt, J=11 and 2x6.5 Hz, 1 H); 5.6 (dt, J=1 1 and 2 xl Hz, 1 H); 3.84 (s, 2H); 3.3 (s, 3H); 3.3 (dd, J=6.5 and 1 Hz, 2H); 2.18(s, 3H); 1.4(s, 6H).
2 7.8(dd,J=7 and 2.5Hz,1H); 7.2-7.55 (m,4H);6.3 (dt, J=16 and 2x6 Hz, 1H); 5.74 (dt, J=16 and 2x1.5 Hz, 1H); 3.8(s,2H); 3.36(s,3H);3.15 (dd, J=6 and 1.5 Hz, 2H); 2.25 (s,3H); 1.46(s,9H).
3 7.8 (dd,J=7 and 2,5 Hz, 1 H); 7.2-7.55 (m, 4H); 6.2 (dt, J=1 1 and 2x6 Hz, 1 H); 5.7 (dt, J=11 and 2x1.5 Hz, 1H); 3.8 (s,2H); 3.38 (s,3H); 3.36 (dd, J=6 and 1.5 Hz, 2H); 2.27 (s, 3H); 1.48 (s, 6H).
4 7.77 (dd, J=7 and 2Hz, 1H); 7.15-7.5 (m,3H); 6.25 (dt, J=16 and 6.5 Hz, 1H); 5.7 (dt, J=16 and 2x1.5 Hz, 1H); 3.76 (s,2H); 3.33 (s,3H); 3.1 (dd,J=6.5 and 1.5 Hz, 2H); 2.2 (s, 3H); 1.44 (s, 6H).
5 7.77 (dd,J=7 and 2 Hz, 1H); 7.2-7.5 (m,3H); 6.14 (dt, J=11 and 6.5 Hz, 1H); 5.65 (dt, J=11 and 2x1 .5 Hz, 1 H); 3.78 (s, 2H); 3.34 (s, 3H); 3.3 (dd, J=6.5 and 1.5 Hz, 2H); 2.22 (s, 3H); 1.44 (s, 6H).
6 8.2-8.4(m,1H); 7.7-7.95 (m,2H); 7.35-7.6 (m, 4H); 6.24 (dt, J=16 and 2x6.5 Hz, 1H); 5.7 (dt, J=16 and 2x1.5 Hz, 1H); 3.88 (s, 2H); 3.58 (qua, J=7 Hz, 2H); 3.14 (dd, J=6.5 and 1.5 Hz, 2H); 2.22 (s, 3H); 1.45 (s, 6H); 1.18 (t, J=7 Hz, 3H).
7 8.2-8.4 (m,2H); 7.7-7.95 (m,2H); 7.35-7.6 (m,4H); 6.12 (dt, J=11 and 2x6.5 Hz, 1H); 5.67 (dt, J=11 and 2x1.5 Hz, 1H); 3.9 (s, 2H); 3.62 (qua, J=7 Hz, 2H); 3.36 (dd, J=6.5 and 1.5 Hz, 2H); 2.25 (s, 3H); 1.48 (s, 6H); 1.2(t,J=7 Hz, 3H).
8 7.77 (dd, J=7 and 2Hz, 1H); 7.3-7.6 (m,4H); 6.28 (dt, J=16 and 2x6.5 Hz, 1H); 5.72 (dt, J=16 and 2x1.5 Hz, 1H); 3.78 (s,2H); 3.6 (qua, J=7 Hz, 2H); 3.14 (dd, J=6.5 and 1.5 Hz, 2H); 2.24 (s, 3H); 1.46 (s, 6H); 1.2 (t, J=7 Hz, 3H).
9 7.76 (dd, J=7 and 2 Hz, 1H); 7.2-7.5 (m, 4H); 6.16 (dt, J=11 and 2x6.5 Hz, 1H); 5.66 (dt, J=1 1 and 2x1.5 Hz, 1H); 3.78 (s, 2H); 3.6 (qua, J=7 Hz, 2H); 3.35 (dd, J=6.5 and 1.5 Hz, 2H); 2.26 (s, 3H); 1.46 (s, 6H); 1.2 (t, J=7 Hz, 3H).
10 8.2-8.4 (m, 1H); 7.7-7.95 (m, 2H); 7.35-7.6 (m, 4H); 6.3 (dt, J=16 and 2x6 Hz, 1H); 6.72 (dm, J=16 Hz, 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); 1.3 (t, J=7 Hz, 3H).
11 8.2-8.4 8.2 1 H); 7.65-7.95 (m, 2H); 7.35--7.65 (m, 4H); 6.12 (dt, J=1 1 and 2x6 Hz, 1H); 6.66 (dm J=11 Hz, 1H); 3.92 (s, 2H); 3.4 (d, J=2 Hz, 2H); 3.36 (dd, J=6 and 1 Hz, 2H); 2.7 (qua, J=7 Hz, 2H); 2.27 (s, 3H); 1.3 (t, J=7 Hz, 3H).
12 8.2-8.4 (m, 1H); 7.65-7.95 (m, 2H); 7.4-7.65 (m,4H); 6.3 (dt, J=16 and 2x6 Hz, 1H); 5.75 (dm, J=16 Hz, 1H); 3.92 (s, 2H); 3.7 (dm J=7 Hz, 1H); 3.18 (dd, J=6 and 2x1.5 Hz, 2H); 2.26 (s, 3H); 2.25 (s, 3H); 1.54 (d, J=7 Hz, 3H).
13 8.2-8.35 (m, 1 H); 7.7-7.95 (m, 2H); 7.35-7.65 (m, 4H); 6.38 (dt, J=16 and 2x6 Hz, 1H); 5.74 (dm, J=16Hz, 1H); 5.4 (d,J#1.5 Hz, 1H); 3.9 (s, 2H); 3.4-3.95 (AB-part of a ABX3-System, JAB=10 Hz, 4H); 3.15 (dd, J=6 and 1.5 Hz, 2H); 2.24 (s, 3H); 1.25 (t, J=7 Hz, 6H).
14 8.15-8.35 (m, 1H); 7.65-7.95 (m,2H); 7.3-7.6 (m, 4H); 6.2 (dt, J=16 and 2x6.5 Hz, 1H); 5.65 (dt, J=16 and 2x1.5 Hz, 1H); 3.86 (s, 2H); 3.1 (dd, J=6.5 and 1.5 Hz, 2H); 2.48 (s, 2H); 2.2 (s, 3H); 1.36 (s, 6H).
15 8.2-8.4 (m, 1H); 7.65-7.9 (m, 2H); 7.3-7.6 (m, 4H); 6.12 (dt, J=11 and 2x6.5 Hz, 1H); 5.62 (dt, J=11 and 2x1.5 Hz, 1H); 3.9 (s, 2H); 3.35 (dd, J=6.5 and 1.5Hz, 2H); 2.46 (s, 2H); 2.25 (s, 3H); 1.36 (s, 6H).
16 7.65-7.85 (m, 1H), 7.1-7.5 (m, 4H); 6.24 (dt, J=16 and 2x6.5 Hz, 1H); 5.66 (dt, J=16 and 2x1.5 Hz, 1 H); 3.75 (s, 2H); 3.1 (dd, J=6.5 and 1.5 Hz, 2H); 2.5 (s, 2H); 2.2 (s, 3H); 1.36 (s, 6H).
17 7.65-7.85 (m, 1H); 7.1-7.5 (m, 4H); 5.16 (dt, J=11 and 2x6.5 Hz, 1H); 5.6 (dt, J=11 and 2x1.5 Hz, 1 H); 3.8 (s, 2H); 3.33 (dd, J=6.5 and 1.5 Hz, 2H); 2.48 (s, 2H); 2.25 (s, 3H); 1.38 (s, 6H).
18 8.2-8.4 (m, 1 H); 7.7-8.0 (m, 2H); 7.35-7.6 (m, 4H); 6.3 (dt, J=16 and 6.5 Hz, 1H); 6.7 (dt, J=16 and 2x1.5 Hz, 1H); 3.9 (s, 2H); 3.15 (dd, J=6.5 and 1.5 Hz 2H); 2.24 (s, 3H); 1.74 (t, J=3.5 Hz, 3H).
19 9.9(t,J=3 Hz, 1H); 8.2-8.4 (m, 1H); 7.7-7.95 (m, 2H); 7.35-7.6 (m, 4H); 6.2 (dt, J=16 and 2x6 Hz, 1H); 5.7 (dt, J=16 and 2x1.5 Hz, 1H); 3.9 (s, 2H); 3.14 (dd, J=6 and 2x1.5 Hz, 2H); 2.4 (d, J=3 Hz, 2H); 2.24 (s, 3H); 1.3 (s, 6H).
20 8.15-8.35 (m, 1H); 7.65-7.95 (m, 2H); 7.3-7.6 (m, 4H); 6.18 (dt, J=16 and 2x6.5 Hz, 1H); 5.65 (dt, J=16 and 2x1.5 Hz, 1H); 3.9 (s, 2H); 3.84 (t, J=7 Hz, 2H); 3.12 (dd, J=6.5 and 1.5 Hz, 2H); 2.22 (s, 3H); 1.7 (t, J=7 Hz, 2H); 1.7 (br, OH); 1.24 (s, 6H).
21 8.2-8.4 (m, 1 H); 7.7-7.95 (m, 2H); 7.35-7.65 (m, 4H); 6.3 (dt, J=1 6 and 2x6 Hz, 1 H); 5.72 (dm, J=1 6 Hz, 1 H); 5.28 (d, J=2Hz, 1H), 3.88 (s, 2H); 3.15--3.65 (m, 4H); 3.14 (dd, J=6 and 1.5 Hz, 2H); 2.22 (s, 3H).
22 8.15-8.3 (m, 1H); 7.65-7.9 (m, 2H); 7.3-7.6 (m, 4H); 6.3 (dt, J=16 and 2x6.5 Hz, 1H); 5.8 (dt, J=16 and 2x1 Hz, 1H); 3.88 (s, 2H); 3.14 (dd, J=6.5 and 1 Hz, 2H); 2.2 (s, 3H).
23 8.2-8.4 8.2 1 H); 7.7-8.0 (m, 2H); 7.4-7.65 (m, 4H); 6.3 (dt, J=16 and 2x6.5 Hz, 1 H); 5.7 (dt, J=16 and 2x1.5 Hz, 1H); 3.9 (s, 2H); 3.14 (dd, J=6.5 and 1.5 Hz, 2H); 2.24 (s, 3H); 1.74 (d, J=7 Hz, 1H); 1.6 (s, 3H); 1.48 (d, J=7 Hz, 1H).
24 8.2-8.4 (m, 1 H); 7.7-8.0 (m, 2H); 7.4-7.65 (m, 4H); 6.16 (dt, J=1 0.5 and 2x6.5 Hz, 1H); 5.66 (dt, J=10.5 and 2x1.5 Hz, 1H); 3.92 (s, 2H); 3,38 (dd, J=6,5 and 1.5 Hz, 2H); 2.24 (s, 3H); 1.76 (d, J=7 Hz, 1H); 1.6 (s, 3H); 1.52 (d, J=7 Hz, 1H).
25 7.78 (dd, J=7 and 2Hz, 1 H); 7.2-7.5 (m, 4H); 6.32 (dt, J=16 and 2x6.5 Hz, 1 H); 5.72 (dt, J=16 and 1.5 Hz, 1H); 3.78 (s, 2H); 3.14 (dd, J=6.5 and 1.5 Hz, 2H); 2.22 (s, 3H); 1.76 (d, J=7 Hz, 1H); 1.58 (s, 3H); 1.46 (d, J=7 Hz, 1H).
26 7.76 (dd, J=7 and 2Hz, 1H); 7.2-7.5 (m,4H); 6.18 (dt, J=10.5 and 2x6.5 Hz, 1H); 5.65 (dt, J=10.5 and 2x1.5 Hz, 1H); 3.80 (s, 2H); 3.34 (dd, J=6.5 and 1.5 Hz, 2H); 2.25 (s, 3H); 1.74 (d, J=7 Hz, 1H); 1.58 (s, 3H); 1.48 (d, J=7 Hz, 1H).
27 7.8 (dd, J=7 and 2 Hz, 1H); 7.42 (t, J=7 Hz, 1 H); 7.2-7.45 (m, 2H); 6.28 (dt, J=1 6 and 2x6.5 Hz, 1H); 5.7 (dt, J=16 and 2x1.5 Hz, 1H); 3.78 (s, 2H); 3.1 (dd, J=6.5 and 1.5 Hz, 2H); 2.2 (s, 3H); 1.74 (d, J=7 Hz, 1H); 1.56 (s, 3H); 1.46 (d, J=7 Hz, 1H).
28 7.78 (dd, J=7 and 2 Hz, 1H); 7.42 (t, J=7 Hz, 1H); 7.2-7.45 (m, 2H); 6.16 (dt, J=10.5 and 2x6.5 Hz, 1H); 5.62 (dt, J=10.5 and 2x1.5 Hz, 1 H); 3.78 (s, 2H); 3.22 (dd, J=6.5 and 1.5 Hz, 2H); 2.2 (s, 3H); 1.72 (d, J=7 Hz, 1H); 1.55 (s, 3H); 1.48 (d,J=7 Hz, 1H).
29 8.2-8.4 (m, 1H); 7.7-8.0 (m, 2H); 7.35-7.65 (m, 4H); 6.18 (dt, J=16 and 2x6.5 Hz, 1H); 5.68 (dt, J=16 and 2x1.5 Hz, 1H); 3.9 (s, 2H); 3.56 (t, J=7 Hz, 2H); 3.34 (s, 3H); 3.12 (dd, J=6.5 and 1.5 Hz, 2H); 2.22 (s, 3H); 1.7 (t, J=7 Hz, 2H); 1.2 (s, 6H).
30 8.2-8.4 (m, 1 H); 7.7-8.0 (m, 2H); 7.4-7.65 (m, 4H); 6.08 (dt, J=1 0.5 and 2x6.5 Hz, 1H); 5.66 (dt, J=10.5 and 2x1.5 Hz, 1H); 3.92 (s, 2H); 3.6 (t, J=7 Hz, 2H); 3.46 (dd, J=6.5 and 1.5 Hz, 2H); 3.43 (s, 3H); 2.24 (s, 3H); 1.74 (t, J=7 Hz, 2H); 1.24 (s, 6H).
31 6.9-7.3 (m, 3H); 6.22 (dt, J=16 and 2x6.5 Hz, 1H); 5.7 (dt, J=16 and 2x1.5 Hz, 1H); 3.4 (s, 2H); 3.36 (s, 3H); 3.05 (dd, J=6.5 and 1.5 Hz, 2H); 2.6-2.95 (m, 4H); 2.2 (s, 3H); 1.65-1.95 (m, 4H); 1.46 (s, 6H).
32 6.9-7.3 (m, 3H); 6.08 (dt, J=1 1 and 2x6.5 Hz, 1 H); 5.66 (dt, J=1 1 and 2x1.5 Hz, 1 H); 3.44 (s, 2H); 3.40 (s, 3H); 3.3 (dd, J=6.5 and 1.5 Hz, 2H); 2.6-2.9 (m, 4H); 2.22 (s, 3H); 1.6-2.0 (m, 4H); 1.5 (s, 6H).
33 8.2-8.4 (m, 1H); 7.7-8.0 (m, 2H); 7.4-7.65 (m, 4H); 6.34 (dt, J=16 and 2x6.5 Hz, 1H); 5.77 (ddd, J=16,2 and 1.5 Hz, 1 H); 4.65 (d, J--2 Hz, 1 H); 3.9 (s, 2H); 3.15 (dd, J=6.5 1.5 Hz, 2H); 2.22 (s, 9H).
34 8.2-8.4 (m, 1H); 7.7-8.0 (m, 2H); 7.3-7.7 (m, 4H); 6.3 (dt, J=16 and 2x6.5 Hz, 1H); 5.76 (dt, J=1 6 and 2x1.5 Hz, 1 H); 3.9 (s, 2H); 3.14(dd, J=6.5 and 1.5 Hz, 2H); 2.22 (s, 9H); 1.84(s, 3H).
35 8.2-8.4 (m, 1 H); 7.7-8.0 (m, 2H); 7.3-7.65 (m, 4H); 6.18 (dt, J=1 0.5 and 2x6.5 Hz, 1H); 5.75 (dt, J=10.5 and 2x1.5 Hz, 1H); 3.95 (s, 2H); 3.4 (dd, J=6.5 and 1.5 Hz, 2H); 2.28 (s, 3H); 2.26 (s, 6H); 1.88 (s, 3H).
36 8.2-8.4 (m, 1 H); 7.7-8.0 (m, 2H); 7.4-7.6 (m, 4H); 6.24 (dt, J=16 and 2x6.5 Hz, 1 H); 5.66 (dm, J=16 Hz, 1H); 3.9 (s, 2H); 3.66 (t, J=7 Hz, 2H); 3.15 (dd, J=6.5 and 1 Hz, 2H); 2.5 (tbr, J=7 Hz, 2H); 2.22 (s, 3H); 2.0 qu, J=7 Hz, 2H).
37 8.2-8.4 (m, 1H); 7.7-8.0 (m, 2H); 7.4-7.65 (m, 4H); 6.1 (dt, J=10.5 and 6.5 Hz, 1H); 5.66 (dm, J=10.5 Hz, 1H); 3.94 (s, 2H); 3.68 (t, J=7 Hz, 2H); 3.38 (dd, J=6.5 and 1.5 Hz, 2H); 2.55 (tbr, J=7 Hz, 2H); 2.26 (s, 3H); 2.03 (qui, J=7 Hz, 2H).
38 8.2-8.4 (m, 1 H); 7.65-8.0 (m, 2H); 7.3-7.6 (m, 4H); 6.24 (dt, J=16 and 2x6.5 Hz, 1 H); 5.67 (dt, J=1 6 and 2x 1.5 Hz, 1 H); 3.9 (s, 2H); 3.55-3.8 (m, 2H); 3.12 (dd, J=6.5 and 1.5 Hz, 2H); 2.22 (s, 3H); 1.8-2.0 (m, 2H); 1.24 (s. 6H).
39 8.2-8.4 (m, 1 H); 7.65-8.0 (m, 2H); 7.3-7.6 (m, 4H); 6.22 (dt, J=16 and 2 x6.5 Hz, 1 H); 5.65 (dm, J=16 Hz, 1 H); 4.7 (dt, J=47 and 2x7 Hz, 2H); 3.9 (s, 2H); 3.12 (dd, J=6.5 and 1.5 Hz, 2H); 2.2 (s, 3H); 1.8 (dt, J=24 and 2x7 Hz, 2H); 1.22 (s, 6H).
40 8.2-8.8 (br, 1 H); 7.2-7.9 (m, 6H); 6.1 (ddd, J=1 6, 8 and 6 Hz, 1 H); 5.54 (dm, J=16 Hz, 1H); 3.6-4.0 (m, 1H);3.36 (s, 3H);3.1-3.4(m,2H);2.2.7 (m, 1H); 1.2-2.3 (m, 7H); 1.44 (s, 6H).
41 8.4-8.9 (br, 1 H); 7.2-7.9 (m, 6H); 5.98 (ddd, J=11,8 and 6 Hz, 1 H); 5.42 (dm, J=1 1 Hz, 1 H); 3.6-4.0 (m, 1 H); 3.26 (s, 3H); 2.8-3.4 (m, 3H); 1.2-2.4 (m, 7H); 1.4 (s, 6H).
The required starting materials may be prepared for example as follows: A) 1-Bromo-6-methoxy-6-methylhept-2-en-4-yne a) 6-Methoxy-6-methylhept-l -en-4-yn-3-ol 20 g of 3-methoxy-3-methyl-1 -butyne are taken up in 200 ml of abs. tetrahydrofuran and added dropwise under inert gas at-20 to 127 ml of a 1.6 m solution on n-butyllithium in hexane. The solution is cooled to-70 and a solution of 11.4 g of acrolein in tetrahydrofuran added dropwise. The reaction mixture is warmed to room temperature, poured onto saturated aqueous NH4CI, extracted with ether, dried and concentrated. The oily pure product is obtained by vacuum distillation at 580/0.2 mbar.
b) 1-Bromo-6-methoxy-6-methylhept-2-en-4-yne (E/Z)-mixture) 12 g of 6-methoxy-6-methylhept-1 -en-4-yn-3-ol are dissolved in ether and 10.5 g of phosphoroustribromide added dropwise at 00. Stirring is continued for 11/2 hours and the mixture then poured onto ice, extracted with ether and the organic phase dried. The crude product thus obtained contains no further starting material (DC (toluene/ethylacetate=9/1): Rf (product) 0.8; Rf (starting material 0.1] and is used directly as etheric solution for the N-alkylation.
The following compounds can be prepared analogously to Aa) or as otherwise hereinbefore described.
6-Ethoxy-6-methylhept-1 -en-4-yn-3-ol (oil; NMR: 5.7-6.2 (m, 1 H); 5.0-5.6 (m, 2H); 4.85 (d, J=4.5 Hz, 1 H); 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; DC [toluene/ethylacetate=9/1]: R1=0.26), 6-Methylthiohept-1 -en-4-yn-3-ol (bp=1 200/1 6 mbar [Balltube]).
6.6-Diethoxyhex-1-en-4-yn-3-ol.
7-Cyano-6.6-dimethylhept-1-en-4-yn-3-ol (oil; NMR: 5.7-6.3 (m, 1 H); 5.0-5.6 (m, 2H); 4.85 (d, J=4.5 Hz, 1 H); 3.1-3.8 (br, OH); 2.55 (s, 2H); 1.4(s, 6H)).
6-Dithioethylenhex-1-en-4-yn-3-ol.
5-(1 -Methyl-2.2-dichlorocyloprop-1 -yl)pent-1 -en-4-yn-3-ol (oil; DC [toluene]: R1=0.15).
6.6-Dimethyl-8-methoxyoct-1-en-4-yn-3-ol.
The following compounds can be prepared analogously to Ab) or as otherwise hereinbefore described.
6-Ethoxy-1 -bromo-6-methyl hept-2-en-4-yne.
6-Ethylthio- 1 -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-dimethylhept-2-en-4-yne.
1 -Bromo-6-dithioethylenhex-2-en-4-yne.
1 -Bromo-5-iodopent-2-en-4-yne.
1 -Bromo-5-(1 -methyl-2,2-dichlorocycloprop- 1 -yl)pent-2-en-4-yne.
1-Bromo-6,6-dimethyl-8-methoxyoct-2-en-4-yne.
B) 1-Bromo-7,7-difluoro-6-methylhepta-2,6-dien-4-yne a) 1-tert.Butyldimethylsilyloxy-4-pentyn-2-ene To a solution of 5 g of 4-pentyn-2-en-1 -ol and 9.3 ml triethylamine in dimethylformamide are added dropwise at room temperature 10.1 g of tert.butyldimethylchlorosilane. Stirring is continued for 1 hour and the mixture poured onto ice and extracted with hexane. The organic phase is washed, dried and concentrated. The crude oily 1 -tert.butyldimethylsilyloxy-4-pentyn-2-ene thus obtained is employed directly in the next reaction.
b) 1-tert. Butyldimethylsilyloxy-6-hydroxyhept-2-en-4-yne 10.7 g of 1 -tert.butyldimethylsilyloxy-4-pentyn-2-ene are dissolved in abs. tetrahydrofuran, 44 ml of a 1.6 m n-butyllithium solution in hexane added dropwise at-50 and then 4 ml of acetaldehyde added at --700. The cooling bath is removed and stirring continued overnight at room temperature. The mixture is then poured onto ice, extracted with ether and worked up conventionally. The oily crude product is chromatographed over silica gel (toluene/ethylacetate=95/5) to obtain 1 tert.butyldimethylsilyloxy-6-hydroxyhept-2-en-4-yne as a colourless oil.
NMR: 6.2 (dt, J=1 6 and 2x3.5 Hz, 1 H); 5.75 (dm, J=1 6 Hz, 1 H); 4.5-4.8 (m, 1 H); 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) 1 -tert.Butyldi methylsi lyloxyhept-2-en-4-yn-6-one A mixture of 6 g of 1 -tert.butyldimethylsilyloxy-6-hydroxyhept-2-en-4-yne and 21 g of MnO2 in dichloromethane are stirred overnight at room temperature and the mixture filtered and concentrated.
The 1 -tert-butyldimethylsilyloxyhept-2-en-4-yn-6-one (oil) thus obtained is directly used in the next stage.
IR: 1665 cm-' (C=O), 2180 cm-1 (C-C).
NMR: 6.6 (dt, J=1 6 and 2x3.5 Hz, 1 H); 5.95 (dt, J=1 6 and 2x2 Hz, 1 H); 4.3 (dd, J=3.5 and 2 Hz, 2H); 2.4 (s, 3H); 0.95 (s, 9H); 0.1(s, 6H).
d) 1-tert-Butyldimethylsilyloxy-7,7-difluoro-6-methylhepta-2.6-dien-4-yne To a solution of 1 g of 1 -tert.butyldimethylsilyloxyhept-2-en-4-yn-6-one and 0.77 ml of dibromofluoromethane in dry dimethylacetamide is added dropwise at 0 a solution of 1.52 ml of tris(dimethylamino)phosphine in dimethylacetamide. Stirring is continued for 12 hours at room temperature whereupon 0.55 g of zinc dust are added. The mixture stirred for 1 hour at 1000, filtered, poured onto ice, extracted with hexane and the organic phase, washed with saturated aqueous NaCI, dried and concentrated. The residue is chromatographed over silica gel (hexane/ethylacetate=1 00/5) to give 1-tert. butyldimethylsilyl-7,7-difluoro-6-methylhepta-2,6-dien-4-yne as a colourless oil.
IR: 1720 cm-'.
NMR: 6.22 (dt, J=1 6 and 3.5 Hz, 1 H); 5.85 (dm, J=1 6 Hz, 1 H); 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-methylhepta-2.6-dien-4-yne 3 g of 1-tert. butyldimethylsilyloxy-7,7-fluoro-6-methylhepta-2.6-dien-4-yne are dissolved in tetrahydrofuran and 1 6.5 ml of a 1 m solution of tetrabutylammoniumfluoride in tetrahydrofuran added at 00. After 2 hour reaction is complete. (DC/toluene: Rf 0.1 compared with Rf 0.9 starting material).
The mixture is poured onto ice, extracted several times with ether, and the organic phase washed with saturated aqueous NaCI, dried and concentrated. The 7,7-difluoro-6-methylhepta-2,6-dien-4-yn-1 -ol thus obtained is dissolved in ether and a solution of 0.5 ml of phosphorous tribromide in ether added dropwise at 00. Reaction is complete after hour (DC/toluene: Rf 0.9 compared with Rf 0.1 starting material). The mixture is poured onto ice and the ether phase isolated, washed and dried and the etheric solution of 1 -bromo-7,7-difluoro-6-methylhepta-2.6-dien-4-yne thus obtained is used directly for further alkylation.
C) 3-Methylmercapto-l -butyne To 15 g 3-methylmercapto-1 -propyne in abs. tetrahydrofuran are added dropwise at-40 113 ml of a 1.6 m n-butyllithium solution in hexane followed by 23.3 ml of trimethylchlorosilane at --700: The cooling bath is removed and the reaction mixture warmed to room temperature and poured onto ice. The mixture is extracted with ether and the organic phase dried and concentrated. The crude 3 methylmercapto-1 -trimethylsilyl-1 -propyne thus obtained is dissolved in abs. tetrahydrofuran, reacted at 700 with 80 ml of a 1.6 m n-butyllithium solution in hexane and 8.7 ml of methyliodide then added dropwise. The cooling bath is removed and one hour later the mixture poured onto ice, extracted with ether, washed with aqueous NaHCO3, dried and concentrated.Ball tube distillation at 700/9 m bar yields 3-methylmercapto-1 -trimethylsilyl-1 -butyne as an oil which is stirred for ca. 45 minutes at room temperature in a solution of 3.3 g of NaOH in methanol and then partitioned between pentane and saturated aqueous NaCI. The organic phase is washed, dried and the pentane removed by column distillation at normal pressure. The title compound is obtained on distillation at 98 -102 as a colourless oil.
D) N-(7-benzo [b]thienyl methyl) methanamine a) 7-Bromomethylbenzo[b]thiophene 7 g of 7-Methylbenzo[b]thiophene are refluxed for 6 hours with 8.5 g of N-bromosuccinimide and a spatula tip of a,a' -azoisobutyronitdle in 50 mi of carbontetrachloride and then cooled, filtered and concentrated. The crude 7-bromomethylbenzo[b]thiophene can be employed directly in the next stage.
b) N-(7-benzo[b]thienylmethyl)methanamine The 7-bromomethylbenzo[b]thiophene is dissolved in dichloromethane, added with stirring to 40 ml of 33% ethanolic methylamine and allowed to stand overnight. The mixture is concentrated and the residue taken up in dichloromethane and extracted with 2N hydrochloric acid. The aqueous phase is made strongly alkaline with NaOH and shaken with dichloromethane. The organic phase is dried with K2CO3, concentrated and the residue vacuum-distilled to give the title compound as an oil b.p.
1030/1.3 m bar.
E) N-(3-Chloro-7-benzo[b]thienylmethyl)methanamine a) 2.3-dichloro-7-methylbenzo[b]thiophene 20 g of 7-methylbenzo[b]thiophene are dissolved in carbon tetrachioride and saturated with chlorine at room temperature. After 2 hours the excess chlorine is removed, the mixture concentrated, and the residue taken up in dichloromethane, washed with saturated aqueous NaHCO3, dried and concentrated.The title compound is obtained on recrystallisation from methanol as colourless crystals m.p. 45-47 b) 3-Chloro-7-methylbenzo [b]thiophene 10 g of 2.3-dichíoro-7-methylbenzo[b]thiophene are dissolved in 200 ml of ether and 28.8 ml of a 1.6 m solution of butyllithium in hexane added dropwise at 0 . After ca. 1 hour the mixture is poured onto dilute aqueous HCl and the organic phase separated, washed, dried and concentrated. The pure oily title compound is obtained by vacuum distillation b.p. 60-62 /0.0013 m bar.
c) N-(3-Chloro-7-benzo [b]thienylmethyl)methanamine Obtained analogously to D).
B.p. 130-132 /0.013 m bar m.p. (hydrochloride 250-255 .
NMR: 7.78 (dd, J=7 and 2.5 Hz, 1 H); 7.25-7.55 (m, 3H); 4.05 (s, 2H); 2.45 (s, 3H); 1.84 (s, NH).
F) 3,3-Dimethyl-5-methoxy-l -pentyne a) 3,3-Dimethyl-1 -pentyn-5-oI 6 g of 3,3-Dimethyl-1 -pentyn-5-al are dissolved in ethanol and reacted under stirring with 1.3 g of sodium borohydride. After 2 hours further stirring the solvent is distilled off and the residue partitioned between ether and aqueous NaCI, and the organic phase dried and concentrated at normal pressure. The title compound is obtained by ball tube distillation at 1 350 as a colourless oil.
b) 3,3-Dimethyl-5-methoxy-1-pentyne To a suspension of 3.5 g of NaH (80%) in tetrahydrofuran are added dropwise at 0 7 g qf 3,3 dimethyl-1 -pentyn-5-ol and after 30 minutes stirring 11 ml of dimethylsulphate slowly added. The cooling bath is removed and stirring continued at room temperature for 3 hours. Excess NaH is broken down with glacial acetic acid and the solvent evaporated under normal pressure. The residue is partitioned between water and hexane and the organic phase washed, dried and concentrated under normal pressure. The title compound is obtained by ball tube distillation at 113-115 as a colourless oil.
G) 1-Bromo-6,6-dimethylthiohex-2-en-4-yne a) 1-tert. Butyldiphenylsilyloxypent-2-en-4-yne Obtained analogously to Ba) as an oil.
NMR: 7.3-7.8 (m, 1 H); 6.34 (dt, J=1 6 and 2x4 Hz, 1 H); 5.9 (dm, J=1 6 Hz, 1 H); 4.24 (m, 2H); 2.9 (m, 1 H); 1.04 (s, 9H).
b) 1 tert.-Butyldiphenylsilyloxy-6-hydroxyhex-2-en-4-yne Obtained analogously to Bb) as an oil.
NMR: 7.3-7.8 (m, 1 OH); 6.24 (dt, J=1 6 and 2x4 Hz, 1 H); 5.9 (dm, J=1 6 Hz, 1 H); 4.4 (dbr, 2H); 4.25 (m, 2H); 1.7 (t, J=7 Hz, 1 H); 1.04 (s, 9H).
c) 1-tert. Butyldiphenylsilyloxyhex-2-en-4-yn-6-al Obtained analogously to Bc) as crystals m.p. 51-59 .
NMR: 9.35 (d, J=1 .5 Hz, 1 H); 7.3-7.8 (m, 10 Hz); 6.62 (dt, J=1 6 and 2x4 Hz, 1 H); 6.18 (dm, J=1 6 Hz, 1 H); 4.34 (m, 2H); 1.06 (s 9H).
d) 1-tert. butyldiphenylsilyloxy-6,6-dimethylthiohex-2-en-4-yne To a mixture of 2 g of 2 g 1 -tert. butyldiphenylsilyloxyhex-2-en-4-yn-6-al and 170 mg of ZnJ2 in absolute ether are added dropwise 2.4 ml of S(trimethylsilyl)methylmercaptan and the mixture stirred overnight at room temperature. It is then poured into water and the ether phase washed, dried and evaporated. The oily raw product is used directly in the next phase.
NMR: 7.3-7.8 (m, 10H); 6.26 (dt, J=16 and 2xHz, 1H); 5.98 (dm, J=16 Hz, 1H); 4.66 (m, 1H); 4.24 (m, 2H); 2.26 (s, 6H); 1.06 (s, 9H).
e) 1-Bromo-6,6-dimethylthiohex-2-en-4-yne Obtained analogously to Be) as an oil.
NMR: 6.35 (dt, J=1 6 and 2x5 Hz, 1 H); 5.84 (add, J=1 6, 5 and 2 Hz, 1 H); 4.67 (d, J=2 Hz, 1 H); 4.24 (dd, J=5 and 2 Hz, 2H); 2.24 (s, 6H); 1.82 (s, 1 H).
H) 1-Bromo-6,6-dimethylthiohept-2-en-4-yne a) 1-Trimethylsilyl-1-butyn-3-oll Obtained analogously to Bb) as an oil. B.p. 100-101 /85 m bar.
b) 1-Trimethylsilyl-1-butyn-3-one Obtained analogously to Bc) as an oil.
NMR: 2.24 (s, 3H); 0.23 (s, 9H).
c) 1-Trimethylsilyl-3,3-dimethylthio-1-butyne Obtained analogously to Gd) as an oil.
NMR: 2.3 (s, 6H); 1.9 (s, 3H); 0.3 (s, 9H).
d) 3,3-Dimethylthio-1-butyne 1 g of 1 -trimethylsilyl-3,3-dimethylthio-1 -butyne is stirred for 2 hour at 0 in a solution of 180 mg NaOH in methanol. Following addition of saturated aqueous NaCI extraction is carried out with Pentane, the organic phase is dried over Na2SO4 and the solvent carefully distilled-off over a Vigreuxcolumn. The oily raw product is used directly in the next phase.
NMR: 2.65 (s, 1 H); 2.2 (s, 6H); 1.8 (s, 3H).
e) 6,6-Dimethylthiohept-1 -en4-yn-3-ol Obtained analogously to Aa) as an oil.
NMR : 5.7-6.0 (m, 1H); 4.9-5.6 (m, 3H); 2.2 (s, 6H); 1.9 (s, 3H); 1.5 (O-H).
f) 1-Bromo-6,6-dimethylthiohept-2-en-4-yne Obtained analogously to Ab).
l) 1-Bromo-8-chloroct-2-en-4-yne a) 3-tert. Butyldlmethylsilyloxypent-1-en-4-yne Obtained analogously to Ba) as an oil.
NMR: 5.76-6.1 (m, 1 H); 5.06-5.55 (m, 2H); 4.8-5.0 (m, 1 H); 2.48 (d, J=2 Hz, 1 H); 0.9 (s, 9H); 0.1 (s, 6H).
b) 3-tert. - Butyldimethylsilyloxy-8-chloroct-1-en-4-yne 2 g of 3-tert.butyldimethylsilyloxypent-1-en-4-yne are dissolved in 10:1 mixture of tetrahydrofuran and hexamethyl phosphoric acid triamide and a 6.2 ml of a 1.6 M n-butyllithium solution in hexane added dropwise at-30 0.98 ml of 1-bromo-3-chloropropane are then added and the reaction solution stirred overnight at room temperature. The mixture is then poured into aqueous NaCI extracted with pentane and the organic phase dried and concentrated. The residue is chromatographed over silica gel (eluant: hexane/ethyl acetate=98/2) and the title compound isolated as an oii.
NMR: 5.7-6.1 (m, 1 H); 4.8-5.5 (m, 3H); 3.6 (t, J=7Hz, 2H); 2.5 (t, 2H); 2.1 (m, 2H); 0.9 (s, 9H); 0.1(s, 6H).
c) 8-Chloroct-1 -en-4-yn-3-ol Obtained analogously to Be) as an oil.
Rf (eluant: toluene/ethyl acetate=4/1)=0.35.
d) 1-Bromo-8-chloroct-2-en-4-yne Obtained analogously to Ab).
J) 1-Bromo-8-chloro-6,6-dimethyloct-2-en-4-yne a) 3,3-Dimethyl-5-(p-toluolsulphonyloxy)pent-1-yne 3 g 3,3-dimethylpent-1-yn-5-ol and 2.7 g triethylamine are dissolved in dichloromethane and 5.1 g of p-toluolsulphonylchloride added dropwise at 00. Stirring is continued for 3 hours at room temperature and the mixture poured into ice-cold aqueous 0.1 N HCI. The organic phase is washed neutral dried and concentrated. The raw product can be used directly in the next phase or chromatographed over silica gel (eluant: toluene).
NMR: 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-dimethylpent-1-yne 2 g of 3,3-dimethyl-5-(p-toluolsulphonyloxy)pent-1 -yne are stirred at 500 overnight and under exclusion of moisture with 1 g of LiCI in DMF. The reaction mixture is distilled and the product obtained between 115-130 used directly in the next phase.
NMR: 3.6, 3.55-3.8 (m, 2H; 2.1 (s, 1 1 H); 1.8-2.0 (m, 2H); 1.24 (s, 6H).
c) 8-Chloro-6,6-dimethyloct-l -en-4-yn-3-ol Obtained analogously to Aa) as an oil.
d) 1-Bromo-8-chloro-6,6-dimethyloct-2-en-4-yne Obtained analogously to Ab) as an oil.
K) 1-Bromo-6,6-dimethyl-8-fluorooct-2-en-yne a) 3,3-Dimethyl-5-fluoropent-I -yne A mixture of 266 mg of 3,3-dimethyl-5-(p-toluolsulphonyloxy)-pent-1 -yne, 5 ml of 1 N tetrabutylammoniumfluoride in tetrahydrofuran and 2 ml of acetonitrile are refluxed overnight. The mixture is then mixed with water, repeatedly extracted with diethylether and the organic phase washed, dried and the solvent distilled off under normal pressure. The resulting crude product is directly used in the next phase.
NMR: 4.70 (dt, J=47 and 2x7 Hz, 2H); 2.05 (s, 1 H); 1.8 (dt, J=24 and 2x7 Hz, 2H); 1.22 (s, 6H).
b) 6,6-Dimethyl-8-fluorooct-1-en-4-yn-3-ol Obtained analogously to Aa) as an oil.
c) 1-Bromo-6,6-dimethyl-8-fluorooct-2-en-4-yne Obtained analogously to Ab) as an oil.

Claims (10)

Claims
1. Compounds of formula I
wherein a) R, represents a group of formula
wherein R5 and R6 represent independently hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, s stands for 3,4 or 5 and x represents oxygen, sulphur, -CH2-, OCH,--, -SCH2-, or -N(R7)- (R7=hydrogen or lower alkyl) and R2 represents hydrogen or lower alkyl or R, and R2 together with the adjacent carbon atom represent a group of formula
wherein pis 1,2or3, R3 and R4 represent independently hydrogen or lower alkyl and R8 represents halogen, acetal or thioacetal, each optionally lower alkyl substituted, halogen alkenyl, halogen cycloalkyl, lower alkylcycloalkyl, or alkyl which is substituted by lower alkoxy, lower alkylthio, lower halogenalkyl, acetal, thioacetal, cyano, formyl or hydroxy whereby hydroxy if present is other than a to the triple bond or b) R3 and R4 together form a (CH2)u group wherein u stands for 3, 4 or 5, R, represents a group of formula Ila, llb or llc, R2 represents hydrogen or lower alkyl and P5 to R8 have the meanings given above, in free base or in acid addition salt form.
2. A compound according to Claim 1 wherein R, is a compound of formula Ila.
3. A compound according to Claim 1 wherein R, is a compound of formula llb.
4. A compound according to any one of Claims 1 to 3 wherein R2 and R3 represent hydrogen and R4 represents lower alkyl.
5. (E)-N-( 1 -naphthylmethyl)-N-methyl-6-ethoxy-6-methyl-1 -hept-2-en-4-ynamine.
6. A compound according to any one of Claims 1 to 5 in free base or in acid addition salt form.
7. A process for preparing a compound according to Claim 1 which comprises reacting a compound of formula Ill
with a compound of formula A-CH2-CH=CH-C=C-P8 in which any functional groups are protected wherein P1, R2, R3, R4 and R8 are as defined above and A represents a leaving group, and if required then removing any protecting groups present and recovering the compound thus obtained in free base or acid addition salt form.
8. A chemotherapeutical composition comprising a compound according to Claim 1 in free base or in chemotherapeutically acceptable acid addition salt form together with chemotherapeutically acceptable diluent or carrier.
9. A method of treating diseases or infections caused by mycetes which comprises administering to a subject in need of such treatment an effective amount of a compound according to Claim 1 in free base or in chemotherapeutically acceptable acid addition salt form.
10. The use of a compound of formula I according to Claim 1 in free base or in chemotherapeutically acceptable acid addition salt form as a chemotherapeutical agent in particular as an anti-mycotic.
GB08312160A 1982-05-07 1983-05-04 Allylamine derivatives processes for their preparation and their use Expired GB2120663B (en)

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US5231183A (en) * 1989-10-02 1993-07-27 Banyu Pharmaceutical Co., Ltd. Process for producing enyne derivatives

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US4751245A (en) * 1986-06-25 1988-06-14 E. R. Squibb & Sons, Inc. Antifungal derivatives of N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine and method of using same
EP0254677A1 (en) * 1986-07-08 1988-01-27 Sandoz Ag Antimycotic 6-phenyl-2-hexen-4-ynamines
NZ227042A (en) 1987-11-27 1991-05-28 Banyu Pharma Co Ltd Substituted alkylamine derivatives and pharmaceutical compositions
GB0003360D0 (en) 2000-02-14 2000-04-05 Novartis Ag Monoclonal antibodies

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EP0024587A1 (en) * 1979-08-22 1981-03-11 Sandoz Ag Propenylamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals

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CH648030A5 (en) * 1980-12-15 1985-02-28 Sandoz Ag BENZOPYRANE ALLYLAMINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE.

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EP0024587A1 (en) * 1979-08-22 1981-03-11 Sandoz Ag Propenylamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5231183A (en) * 1989-10-02 1993-07-27 Banyu Pharmaceutical Co., Ltd. Process for producing enyne derivatives
US5296612A (en) * 1989-10-02 1994-03-22 Banyu Pharmaceutical Co., Ltd. Process for producing enyne derivatives
US5440049A (en) * 1989-10-02 1995-08-08 Banyu Pharmaceutical Co., Ltd. Process for producing enyne derivatives

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IT8348233A0 (en) 1983-05-06
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FR2526423A1 (en) 1983-11-10

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