CA2106892A1 - 5-oxo-dibenzo(a,d)cyclohepta-1,4-dienes - Google Patents

5-oxo-dibenzo(a,d)cyclohepta-1,4-dienes

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Publication number
CA2106892A1
CA2106892A1 CA002106892A CA2106892A CA2106892A1 CA 2106892 A1 CA2106892 A1 CA 2106892A1 CA 002106892 A CA002106892 A CA 002106892A CA 2106892 A CA2106892 A CA 2106892A CA 2106892 A1 CA2106892 A1 CA 2106892A1
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Hanno Wild
Jutta Hansen
Jorg Lautz
Arnold Paessens
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Bayer AG
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Abstract

Abstract 5-Oxo-dibenzo[a,d]cyclohepta-1,4-dienes The invention relates to substituted 5-oxo-di-benzo[a,d]cyclohepta-1,4-dienes of the general formula (I)

Description

The invention relates to 5-oxo-dibenzo[a,d]cyclohepta-1,4-dienes, processes for their preparation and their use as retroviral agent~.
.
Cis/trans-10,11-dihydroxy~5-oxo-di~enzo[a,d]cyclohepta-1,4-diene and the corresponding diacetates are already :
known from the publication in Bullo SOc~ Chim. Fr.
(1960~, 400.

The present invention now relates to substituted 5-oxo- .
dibenzo[a,d]cyclohepta-1,4-dienes of the general formula (I) O

RlR2N-H2~ ~`CH2-N~3R4 RsO OR6 :

.
in which and~R3 are ~identical or dif~erent a~d represent an : ~ amino-protective group or repre~ent a group of the formula R7-Co-, :
. .
: 15 ln whiah R' denotes hydrogen, trifluorome~hyl, or straight~
ahain or brancbed alkoxy having up to 8~carbon ' ' , . . .
: ~.
~ - 1 - . .
.. . .
'."',, ' '
2 3 18 9 7 5 4 6 atoms or alkyl having up to 18 carbon atoms, which are optionally substituted identically or differently up to 2 times by aryl having 6 to 10 carbon atoms or pyridyl, or S deno~es aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, tri-fluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl having up to 8 carbon atom8 r denotes cycloalkyl having 3 to 7 carbon atoms, or denotes quinolyl, quinolyl N-oxide, indolyl, pyridyl, morpholino or piperazinyl, or denote~ a residue of the formula R8 R8 .. ..
r Rg-Y-CH2-CH- Rlo-CO-O-CH-~R8 ' ~: :
. .': , Rl1-S(O)m-~nH-CH- ,T-~ -(CHJp- , ;~

o R8 ' or Rl2 - P-(CH2)s-CH-: . R13 .. :-in which .
5 R3 denote~ phenyl or naphthyl, ~ ~

.. ', ~,' .. . .
. . Le A Z9 325 - 2 ~
: .
- , .

. .

fi~2 23189-7546 .

R9, Rl and Rl', independently of each other, denote :
straight-chain or branched alkyl having up to -14 carbon atoms, which is optionally substituted by phenyl or naphthyl, or denote aryl having 6 to 10 carbon atoms, which for its part is optionally substituted by alkyl having up to 4 carbon atoms, or Rl denotes a residue of the formula O ~ N (CH2)2-N -CH3 ::

m denotes a number O, 1 or 2, T denote~ morpholino or cyclohexyl, p denotes a number 1, 2 or 3, :~

Y and Y', independently of each other, represent CO-or 52-t ;~ ~

t denot2s a num~er O or 1, ~5 Rl2 and R'~j independently o~ each other, repre~ent hydroxyl or alkoxy having up to 8 carbon atoms, -, ropresents a number 1 or 2, ~ -R2 and R4 are identical or diffcrent :and represent ,' ' :

, Le ~ 29_325 - 3 -2~ 9~2 hydrogen, or straight-chain or branched alkyl having up to 8 carbon atoms, Rs and R6 are identical or different and repr~sent hydrogen, or represent straight-chain or branched acyl or alkoxycarbonyl having in each case up to 8 carbon atoms, or represent a hydroxyl-protective group, and in the case that either Rs or R6 represents hydrogen, ' ':
in the form of their hemiacetals and salts thereof.

Physiologically acceptable salt~ of the substituted 5-oxo-dibenzoCa,d]cyclohepta-1,4-dienes can be salts of the compounds according to the invention with mineral acids, carbox~lic acids or sulpho~ic acids. Those which are particularly preferred are, e.g., salts with hydro-~ chloric acid, hydrobromic acid, sulphuric acid, phosphoric~acid, methanesulphonic acid, ethanesulphonic : acid, toluene~ulphonic acid, benzenesulphonic acid, nahphalenedi~ulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, : maleic:acid or:benæoic acid.

: : Salts with customary base , such as~ for example~ alkali :metal ~alts (e.g. ~odium or potaE8i~m ~alt~, alkaline earth metal ~altB ~e.~. calcium or magnegium 8alt8) ~ or ~ ammonium salts, derived from ammonia or organic amlnes ~
: 25 : such a~, for example, d1ethylamine, triethylamine, ~ ~ ';.'"'' .
' . . .

.;,. .
Le A 29 325 - 4 - -2 ~ 9 ~ `

ethyldiisopropylamine, procaine, dibenzylamine, N-methyl-morpholine, dehydroabietylamine, 1-ephenamine or methyl-piperidine, can be mentioned as salts.

The compounds according to the invention can exist in stereoisomeric form~ which either do (enantiomers) or do not (diastereomers) relate to each other as image and mirror image. The invention relates to both the antipodes and the racemic forms, as well as the diastereomeric ~ mixtures. The racemic forms as well as the diastereomers can be ~eparated in a known manner into the stereisomeri-cally homogeneou~ components [cf. E. L. Eliel, Stereo-chemistry of Carbon Compounds, McGraw ~ill, 1962].

Within the scope of the invention, amino-protective groups are the customary ami~o-protective groups which are u~ed in peptide chemistry.

These preferably include: b2nzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxy-carbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitro-benzyloxycarbonyl, 2-nitro-4,'i-dimethoxybenzyloxy- `
carbonyl, methoxycarbonyl, ethoxycarbonyl, propoxy-carbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxy-carbonyl, tert-butoxycarbonyl, allyloxycarbonyl, vinyl-oxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-tri-methoxybenzyloxycarbonyl, cyclohexoxycarbonyl, l,l-dimethylethoxycarbonyl, adama~tylcarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-Le A 29 325 - 5 -':, ' ' ' . ' ;, ," '' '.'' " '' " '' ~ "'; ,'' ' '' ~ . ' .. . ..

~ 7 butoxycarbonyl, menthyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloro-acetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxy-methylene, 4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitro-phenyl.

In the residue of the formula (II), O

(II) RsO OR6 the groups -ORs and -oR6 can be located in the cis- or -~
trans-position in relation to each other or can be present as a ci~/trans isomer mixture.

The de~inition of the hemiacetal form is illustrated by way of example by the residue of the formula (IIa):
OH .
~ :.
(~a) OH

Hydroxyl-protective group generally represents trimethyl- :
silyl, triethylsilyl, triisopropylsilyl, tert-butyldi- :

Le A 29 325 - 6 -:" :. ,: . . . :, methylsilyl, triphenylsilyl, trimethylsilylethoxy-carbonyl, benzyl, benzyloxycarbonyl, 2-nitro~enzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxy-carbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 4-S methoxybenzyloxycarbonyl, formyl, acetyl, trichloro-acetyl, 2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxy-carbonyl, 2,4-dimethoxybenzyloxycarbonyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, [2-(trimethyl-silyl)ethoxy]methyl, 2~(methylthiomethoxy)etho~ycarbonyl, tetrahydropyranyl or benzoyl.
Those which are preferred are trimethylsilyl, triethyl-silyl, triisopropylsilyl, tert-butyl-dimethyl~ilyl, triphenylsilyl, benzyloxycarbonyl, 4-nitrobenzyloxy-carbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl and trichloro-acetyl.
. .
The compounds of the general formula (I) are preferred in which -:

R1 and R3 axe identical or different and represent benzyl-oxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-nitrobenzyloxycarbonyl, ~luorenyl-9-methoxycarbonylor2,2,2-trifluoro- ~:
acetyl, or represent a group of th~ formula R'-CO-, -;~.

R7 denotes hydrogen, trifluoromethyl, or straight-Le A 29 ~25 - 7 -,,, ,, . . ,,, , ,. .,, : . ~ ~ ., , ;, , , , . " ,., ;,, ., ., , , . : , , : , , .

chain or ~ranched alkoxy having up to 4 carbon atoms or alkyl having up to 16 carbon atoms, which are optionally substituted identically or o differently up to 2 times by phenyl, naphthyl or pyridyl, or denotes phenyl or naphthyl, which can be optionally substituted by fluorine, chlorine, :. :
trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl having up to 6 carbon atoms, :
denotes cyclopropyl, cyclopentyl, cyclohexyl, quinolyl, quinolyl N-oxide, indolyl, pyridyl, morpholino or piperazinyl, or denotes a re~idue of the formula -~
~R8 ~R8 .`.~ :
R9-Y-CH2-CH- Rlo-CO-O-CH- , or : R8 .' .
Rll-StO)m-NH-CH~

~: in which .:
Y denotes the CO or S2 group, R8 denotes phenyl or naphthyl, j,~
: :~.3 ,~ Rl and R11, independently of each other, :
,~.:

~ .

,.~ .
~ Le A 29 325 - 8 - .
- .. ..

.,:

represent straight-chain or branched alkyl having up to 8 carbon atoms, tolyl, phenyl or naphthyl, or R~ denotes a residue of the formula O N-(CH2)2-N - :

m denotes a number 1 or 2, R2 and R4 are identical or different and represent -hydrogen, or straight-chain or branched alkyl having up to 6 carbon atoms, .
Rs and R6 are identical or different and represent 10hydrogenr:or represen~ straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 -:
carbon atom~ or : :represent trimethylsilyl, triethylsilyl, trii~o- ~
propylsily1, tert-butyl-dimethyls1lyl, triphenyl- - -155ilyl ~ benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, : tert-butoxycarbonyl, allyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, formyl, acetyl or trichloro-acetyl, ~ and in the case that either Rs or ~6 represents hydrogen, : 20 : in the orm of their hemiacetal~ and ~alts thereof.

' ' ', ' , Le A 29 325 ~ - 9 -' ~', .
.:: ', . ' , . ,. ;,, . : . ,, :: . .: . , .. , . : . ., : .,. ,, , .,: . . . .

' ' ' i . . ' ' , ,~ ' , , ' .,, ! ~, '~ . .. .

o ~

The compounds of the formula ( I ) are particularly preferred in which Rl and R3 are identical or different and represent benzyl oxycarbonyl, 4-methoxybenzyloxycar~onyl, 4-nitro-benzyloxycarbonyl,tert-butoxycarbonyl,allyloxycarbonyl, 2-nitrobenzyloxycarbonyl, fluorenyl-9-methoxycarbonyl or - : .
2,2,2-trifluoroacetyl, or repre~ent a group of the foxmula R7-Co- .
in which :

R7 denotes hydrogen, trifl~oromethyl, or straight-chain or branched alkoxy having up to 4 and alkyl having up to 14 carbon atoms, which are : -:
optionally substituted up to 2 times by phenyl, ..
naphthyl or pyridyl, or : denotes phenyl or naphthyl, which can optionally `
be subs ituted by fluorine, chlorine, trifluoro- ~:
methyl, trifluorom~thoxy, or by straight-chain or branched alkyl having up to 4 carbon atoms, `-denotes cyclopropyl, cyclopentyl, cyclohexyl, ` .-: quinolyl, quinolyl ~-oxide, indolyl, pyridyl, : morpholino or piperazinyl, or denote~ a residue ~ of the formula : ', ':
:

Le A 29 325 - 10 -, :.

. ~. . ,, ' ' ' ' ' ' , . '' , ' ' ,. ' .', . " . . . . . . ' ' . ", ' ' . ' ,' .. ~ ; : ,' ' ' .

~ R~ ~R8 R9-Y-CH2-CH- or Rlo-CO-O-C~- -in which -:

Y denotes the CO ox SO2 group, R~ denotes phenyl or naphthyl R9 and R', independently of each other, represent straight-chain or branched alkyl having up to 4 carbon atoms, tolyl, phenyl or naphthyl, R~ represents a residue of the formula, o N-tCH2)z-N -: ~ CH3 :~ .
: . . .
R? and R4 are identical or ~different and ~represent 10: ~ hydrogen, or straight-chain or branched alkyl having up to 4 carbon~atoms, ~ :~

: ;Rs and R6 are~ identical or differen~ and represent : hydro~en, or represent:straight-chain or branched acyl~or~alkoxycarbo~yl having in ea~h case up to 15 : 4 carbon atoms, or represent trimethylsilyl, triethylsilyl, tri-isopropylsi1yl, tert-butyl-dimethylsilyl, tri-phenylsilyl,benzyloxycarbonyl,4-nitrobenzyloxy-: .
. ': ' : : ~ L~ A 2g 325 - 11 -::
' ~ 23189-7546 carbonyl, tert-butoxyearbonyl, allyloxycar~onyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl or trichloroacetyl, and in the case that either R5 or R6 represents hydrogen, in the form of their hemiacetals and salts thereof.
" "

In addition, a process has been found for preparing the compounds of the general formula (I) according to the invention, characterised in that - :
compounds of the general formula (III) o ;~.~'vi' ll : .. ..
Rlc-HN-H2C~CHz-NH R

in which X is a leaving group, for example bromine, chlorine, mesyl or tosyl, of which bromine is preferred, . .

Rl4 and Rl5 are identical or different and represent an .-amino-protective group, prefera~ly phenylmethoxy- .
:~ car~onyl,~ .
: .. - .', . .' ~ are firqt converted by reactions wi.th carboxylic acids of 15~ the general formula (IV) - :
'~
Rl6-co2H . (IV) ;;

in whLch ~; , ., .: . .
'. :'."'". ' '.' .' ~

Le A-29 325 ~ 12 - :
.. , :

~fi~9~

R16 includes the respective range of meaning listed above for the su~stituents Rs and R6, with the exception of hydrogen, and in the presence of a corresponding salt, into the compounds of the general formulae (Ia) and (Ib) ~ :

R,4-HN-H2C ~ CH2-NH-R'5 (Ia) R160 Oi~

o ~-HN-H2C' ~ CH2-NH-Rls (Ib) R~,O OH

in which : R14 and Rl5 have the abovementioned meaning, ~ : ~ R16 likewise has the abovementioned meaning, but prefer-ably repFesents acetyl~, ',;,- , ~the hydroxyl unction lR5/R6=~) i8 subsequently liberated by hydrolysis~

and in the ca~e of the remaining substituent~ listed ~: ~ :above under R1 and R3, .'. ' , ' .`' ":

; .~
:; .

Le A 29 325 - 13 - ~

.. . . . .. . . .

~ ~6~92 the radlcals R14 and Rls are first eliminated according to customary methods, preferably by hydrogenation, to liberate the amino function, and are reacted, in a last step, with compounds of the general formula (V) -Rl7-Co2H ( V ) in which Rl7 embraces the range of meaning of the above-listed su~stituents Rl and R3, in inert ~olvents, in the presence of a base and/or of an auxiliary compound, optionally with prior activation of .:.
the carboxylic acid function. -:

The process according to the invention can be illustrated, by way of example, by the following formula I5 scheme:
o o Z-HN ~ NH-Z Z-HN~NH~
A6:0 OAs ~oO 01~1 -NaOH, EtOH ¦ 81%
: ' .. . .
:. . .

Le A 29_325 - 14 - :`

fi~9~

Z HN~ ~ Z-HN~ ~NH-Z
HO OH
HO OH
Hj~, Pd-C

Z = - C-O-CH2-C6Hs 2 X IH3C)3C-02S ~ :

H2N~ ~ DCC, HOBT D
HCI OH

; ' ' ' ' '.". , : .
' ~' . . .
- ' .
~' ' '''~
Le A 7, 9 3 2 5 - 15 - ~

. , ,, ' .,..~ , ,.

-I~,C~,C~,S~.S4~C(C~, ~

The reaction with the carboxylic acids of the general formula (IV) generally takes place within a temperature ~:.
range of -20C to 80C, pre~erably of 0C to -~40C, and under atmospheric pressure.
, ':
Acetic acid/silver acetate, propionic acid/silver :`
propionate, or butyric acid/silver butyrate are in general suitable a~ the carboxylic acidi~alt sy6tem.
Acetic acid/~ilver acetate is preferred.

The cu~tomary inorganic bases are ~uitable bases for the ~:
hydrolyæi~. ~hese prefera~ly include alkali metal .:~
: : hydroxide~ or alkalin~ earth metal hydroxides, such as, - ~ :
for example, Yo~ium hydride, potassium hydroxide or . ~
barium hydroxide:, or aLkali carbonate~, such a~ sodium or ; ~ pota~ium carbonate or sodium hydrogen carbonate. Sodium ;:
~hyd~oxide or pota~ium hydroxide are particularly preferably employed.
.
Water, or the organic solvent~ which are customary for hydrolysis, are ~uitable ~olvent~ for the hydrolysi~. :

' ~';,..

Le A ~9 ~25 - 16 -' :

These preferably include alcohols, such as methanol, ethanol, propanol, isopropanol or butanol, or ethers, such as tetrahydrofuran or dioxane, or dimethyl~ormamide or dimethyl sulphoxide. Alcohols, such as methanol, ethanol, propanol or isopropanol, are particularly preferably used. It is likewise possible to employ mixtures of the said solvents.

The hydrolysis is generally carried out within a temperature range of 0C to +100C, preferably of +20C
to +80C. -::
In general, the hydrolysis is carried out under atmospheric pres6ure. However, it is also possible to employ reduced pressure or ele~ated pressure (e.g. from 0.5 to 5 bar).

In carrying out the hydrolysis, the base is generally employed in a quantity of 1 to 3 mol, preferably of 1 to 1.5 mol, based on 1 mol of the ester. Equimolar quan-tities of the reactants are particularly preferably used.
~, .

The elimlnation of the amino-protective groups (R'4/R's) takes place in a manner known per e under acidic or basic conditions, or reductively by catalytic hydrogena-tion, for example u~ing PdtC in organic ~olvents such as ethers, e.g. tetrahydrofuran or dioxane, or alcohols, e . g . methanol, ethanol or isopropanol.

The hydrogenation generally takes place within a ' ' .'. ':

Le A 29 325 - 17 ~

. . , , ; :. , ,. . .. .: , . " , , , .: ~. ::., . : . . .

211 ~fi~

temperature range of 0C to 80C, preferably of 0C to 40C.

In general, the hydrogenation is carried out under an elevated pressure of 2 bar to 8 bar, preferably of 3 to 5 bar.

The customary inert solvents which are not altered under the reaction conditio~s are suitable solvents for the reaction with th2 compounds of the general formula (V).
These pref~rably include organic solvents such as ethers, e.g. diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons, such as benzene, toluene, xylene, cyclohexane or petroleum fractions, or halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl ~ulphoxide, dimethyl formamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline. It is likewise possible to use mixtures of the said solvents. Dichloromethane, chloroform, dimethyl-formamide or tetrahydrofuran are particularly preferred.
.. .
As~auxiliary compounds, condensing agents are preferably employed and can al80 be base~, in particular if the carboxylate group is present in activated form a~ the :
anhydride. In this instance, the customary condensing agents are pre~erred, ~uch as carbodiimide~, e~g. N,Ni-25 diethyl-, N,N'-diisopropyl- or N,N'-dicyclohexylcarbo-diLmite, N-(3-dLmethylamlnoisopropyl)-N'-2thyl-carbodiLm1de hydrochloridej or N-cyclohexyl~N'-(2-morpholinoethyl)-': ' Le A 29 325 - 18 -.. . .,. , , :,.. . . . . ...

~fi~

carbodiimide metho-p-toluenesulphonate, or carbonyl compounds, such as carbonyldiimidazole, or 1,2~oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl~5-methyl-isoxazolium perchlo-rate, or acylamino compounds, such aæ 2-ethoxy-1-ethoxy~
carbonyl-1,2-dihydroquinolin~, or propanephosphonic anhydride, or isobutyl chloroformate, or benzo-triazolyloxytris(dimethylamino)phosphonium hexafluoro-phosphate, or 1-hydroxybenzotriazole. ~ -In addition, alkali metal carbonates, e.g. sodium or -potassium carbonate or sodium or potassium hydrogen carbonate, or organic bases, such as trialkylamines, e.g.
triethylamine, ethyldiisopropylamine, N-ethylmorpholine, N-methylpiperidine or N-methylmorpholine can be employed, -for example. N-methylmorpholine is preferred. -~

The auxiliary compounds and bases are employed in a quantity of 1.0 mol to 3.0 mol, preferably 1.0 to 1.2 mol, based on~ in each case, 1 mol of the compounds of the general formula (V).
: .
The reactio~s are carried out within a temperature range 0~ o30C to 100C, preferably at 9C to 30C, and under atmospheric pressure.

The reaction~ can be carried out both under atmospheric pressure and;under elevated or reduced pres~ure (for example 0.5 to 5 bar~, preferably under atmospheric presæure~ , Le A 29 325 - 19 - ~

;

~fi~92 .: ' The compounds of the general formulae (IV) and (V) are known or can be prepared according to customary methods. .
.: :.
The compounds of the general formulae (Ia) and (Ib) are novel and can be prepared as deseribed above.

The compounds of the general formula (III) are likwise novel and can be prepared by first reacting 2,8-bis-azidomethyl-5-oxo-di-benzo[a,d~cyclohepta-1,4,6-triene of the formula (VI), O :, N3-~zC ~ ~ CH~-N

: after having been taken up in ethers, preferably in T~F, .
lQ with triphenylphosphine/water with the formation of the diamine, a~d subsequently with compounds of the general formula (VIIa) or (VIIb) -Rl8-CO~ (VIIa) Rl9-CO-Cl ~VIIb) 15 in whiah Rl8 and R19 embrace the above-listed range of meaning for the radicals Rl4/R1s, .

Le A 29 325 - 20 -':' . ' , . . .

' ' ' ' ,, ' ' . ' ', ' ' " ' ' ' ,. "' ' ' ' ' , in inert solvents, in the presence of a base and an auxiliary compound, and, in the case of the carboxylic acids (VIIa), with prior activation of the carboxylic acid function, and, in a last step, carrying out a bromination with elemental bromine in inert solvents.

The reaction with triphenylphosphine/H2O takes place within a temperature range of 0C to +50C, prefexably at room temperature, and under atmospheric presRure.

The reaction with the compounds of the general formula (VII) is effected in analogy with the description, set out above, of the reaction with the compounds of the general formula (IV).
, The bromination takeR place in halogenohydrocarbon/ : -15 glacial acetic acid mixtures, prefe:rably dichloromethane/
glacial acetic~acid, and at room tlemperature.

~: The compound of the formula (VI) is likewise novel and can, for exam~le, be prepaxed by first conYerting 2~8 dimethyl-5-oxo-dibenzora,d]cyclvhepta-1,4,6-trieneofthe ~onmula (VIXI), :' H3C ~ CH3 CV~

: '; .
~ :' Le A 29 325 - 21 - ~ ~
, ;..,.::::
'' 2~0~2 as described above, by reaction with N-bromosuccinimide in one of the above-listed solvents, p~eferably carbon tetrachloride, and while irradiating, into the compounds of the formula (IX) O .:. "

Br ~ Br and, in a following step, reactins with lithium azide in dimethyl sulphoxide.

The bromination proceeds within a temperature range of ~50C to +120C, preferably of +70C to ~100C.

The reaction with lithium azide is generally carried out within a temperature range of 0C to +70C, pre~erably at room temperatureO

The compound of the formula (IX) is noval and i~ prepared as described above. ::.

The compound of the formula (VIII) is novel and canj for .
example, be prepared by first converting 4-methyl-2-[2-(3-methylphenyljethyl]benzoic acid of the foxmul2 (X~, 1l3c~c~3;~cn3 a~

by reaction with polyphosphoric acid in sulpholane, into .
:

La A 29 325 - 22 - ~

.
,:, , , . , , . . ~ . , . , , :

, ,, . ... , 2~ ~6~2 the compound of the formula (XI) O
H3C = CH3 (X~ ~ :

and, in a following step, as already described several : :
times, brominating with N-bromosuccinimide in carbon ;:
tetrachloride, while irradiating, and subsequently S eliminating hydrogen bromide under the influence of a -base.

The reaction to give the compounds of the formula (X) proceeds within a temperature range of +20~C to ~120C, preferably o~ ~60C to ~100C, for the bromination, and ~20C to +60C for the elimination. - :~

The elimination occurs in an inert solvent, preferably dimethylformamide. Preferred bases are DBN, DBU and ; DABCO.

The compound of ~ormula (XI) i~ novel and can be prepared ~: 15 as described above. ~ ~

The~compound~of formula (X) is likewise novel and is : :
prepa~ed by ~eacting 2~4-dimethylbenzoic acid, in a : :
LDA/T~F/n-hexane solution, with 3-methylbenzyl bromide.
:: . . .
: The~;:reaction takes plaae wit~in a temperature range of :~
-40C to +40C, preferably of -30C to +20C.

: , : i: ' ~: '' :' Le A 29 325 - 23 ,' ~
,:

~, ,, ~ , , , ,; , , . . . : "~ .

2 ~

The inhibitors described here are inhibitors of HIV
protease and, as such, may be employed for all purposes for which enzyme inhibitors are suitable. This is, for example, their employment in diagnosis in order to improve the precision and selectivity of enzyme activity measurements. They can serve as affinity labels in affinity chromatography and can be used in research to elucidate reaction mechanism~ and the specificity of enzymic reactions.

Besides this, it has been found, surprisingly, that the compounds of the general formula (I) possess an exceptionally strong effect on retroviruses. This is verified by means of an HIV-specific protease enzyme test.

The results of the examples listed below were determined according to the HIV test ~ystem described in the following references [cf. Hansen, J., Billich, S., Schulze, T., Sukrow, SO and Molling, K (1988), EMBO
Journal, Vol. 7, No. 6, pp. 1785 ~ 1791]: purified HIV
protease was incubated with synthetic peptide which imitate~ a cleavage ~ite in the Gag precursor protein a~d represents an in-vivo cleavage ~ite for the ~IV protea~e.
The cleavage products o~ the synthetic peptide which resulted were analysed by means of rever~e phase high performancs liquid chromatography (RP-HPLC). The ICso value~ which are given refer to the substance concent-rations which, under the test conditions ~et out above, effect a 50% inhibition of the protea~e aativity.

Le A 29 325 - 24 -, , , , , . , :: :: : ., . ,,. , ,, .. , , : , ,. .. ~ ." ~, , :. :
: . :,. , : . : . , ... " ". ., , , .... : .. ...... . . ... . . ..

7, Table 1:
_ _ Exp. No.ICso (~m) l . . Il _ _6 0.005 In addition, the compounds according to the invention showed an effect in lentivirus-infected cell cultures. It was possible to demonstrate this using the HIV virus as ex,~mple~, HIV infection in cell culture The ~IV test was carried out, with minor modifications, according to the method of Pauwels et al. [cf. Journal of Virological Methods 20, ~1988), 309-321~.

Normal human blood lymphocytes (PBLs) were enriched through Ficoll-Hypaque and stimulated in RPMI 1640, 20%
~etal calf serum containing phytohaemagglutinin (90:~g/ml) and intPrleukin-2 (40 U/ml). For infection with the infectious HIV, the PBL~ were pelleted and the cell pellet was subsequently suspended in 1 ml of HIV
virus adsorption solution and incubated at 37C for 1 hour.
.: .
The viru3 ad~orption solution wa~ centri~uged and the infected cell pellet was taken up in growth medium in such a way that the RuBpen8ion was adjusted to 1 x 105 ~:.

:"',. ' ' ''':

Le A 29 325 - 25 - ~

. .

', .~,"', ., ,,' ." ', ,. ', , ' ; ' " ', ," ' ' ", " :"' "" ,, ' . ' 210~ ?

cells per ml. The cells infected in this manner were pipetted, at 1 x 104 cells/well, into the wells of 96-well microtitre plates.

The first vertical row of thP microtitre plate contained only growth medium and cells which were not infected but which otherwise had been treated exactly as described ahove (cell control). The second vertical row of the microtitre plate contained only HIY~infected cells (viru~
control) in growth medium. The remaining wells contained the compounds according to the invention in different concentrations, starting from the wells of the 3rd vertical row of the microtitre plate, from which the substances under examination were diluted 2'-fold in doubling steps.

The test mixtures were incubated at 37C until the syncytium formation which is typical for ~IV appeared in the untreated virus control (between day 3 and 6 after infection) and it was then evaluated microscopically.
Under the~e ~est conditions, about 20 syncytia re6ulted in the untreated viru~ control while the untreated cell control contained no syncytia.

The ICso values were determined as the concentration of the compound according to the invention at which 50~i (about 10 syncytia) of the virus-induced syncytia were suppressed ~y the treatment with thi~ compound.

It has now been found that the compounds according to the Le A 29 325 - 26 -.

, ::. ' ~ :, .: ' ~

.9 2 invention protect HIV-infected cells from virus-induced cell destruction. : .
Ta~le 2 . _ .
Exp. No. IC50 (~m) _ _ : .
The compounds according to the inventio~ represent : :
valuable active compounds for the treatment and :.
prophylaxis of diseasec caused by retroviruses in human and veterinary medicine. :: .
.
: Ranges of indications in human medicine which may be mentioned by way of example are: .
.....
1.) The treatment and prophylaxis of human retrovirus infections.
: 15 2.) For the treatment or prophylaxis of diseases (AIDS) :; :
: : ~ caused by HIV I (human immunodeficiency viru~;
previously termed HTLV III/LAV) and HIV II, and the stage~ associated therewith~ such as ARC (AIDS-~ related complex) and ~AS ~lymphadenopathy syndrome), 2 0 ~ a~ well a8 the immu~odeficiency and encephalopathy ;:
caused by thi_ viru~
: 3. ) For the treatment and prophylaxi~ of an H~LV~I or HTLV~ nfection.
4.) For~ the treatment or the prophylaxis of the ~' ."- ,.
.. :: :...:
~ ~ .
L~_A 29 325 - 27 -,~,. .

.. ~ .
.

., .: " , " . :, ~, .. , , i , ~, ,, ," "" ,.,, . ,., ," ", ", " ., ., .. ", , . ,~, , ,~
- ~ : : , , ", .,., . ~ ,, . ,i . . .

~ ~ ~ fi ~ ~ ~ 23189-7~46 AIDS-carrier state.

Indications in veterinary medicine which may be listed by way of example are:

Infections with a) maedi-visna (in sheep and goats) b) progresslve pneumonia virus (PPV) (in sheep and goats) c) caprine arthritis-encephalitis virus (in sheep and :~:
goats) d) zwoegerziekte virus (in sheep) e) equine infectious anaemia virus f) infections caused by the feline 10ukemia virus g) infections caused by the feline immunodeficiency virus (FIV) 5 h) infections caused by the simian immunodeficiency virus (SIV) Of the range of indica~ions in human medicine, the above-listed points 2, 3 and 4~are preferred.

Pharmaceutical preparations which, besides non-toxic, inert pharmaceutically suitable exaipients, contain one or more compounds of the fonmula (I)/~Ia~/~Ib), or which are compo.ed of one or more active compound~ of the formula (I)/(Ia)/~Ib), a~ well a~ processes for preparing these preparations, are `also included in the present invention.

The invention also extends to commercial packages containing a compound of the inVentiQn, together with ins.tructions for its use in combating retroviruses.

Le A 29 325 - 28 -.... ~ . , , .. , , : . ~, ....... .. . . . . . . .. .. . .... . . . . . .. . ... . . .

~ ~fi~9~ :

The active compounds of the formula (I)/(Ia)/(Ib) should preferably be present in the above-listed pharmaceutical preparations at a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95, % by weight of the total mixture.

As well as the compounds of the formula (I)/(Ia)/(Ib), the above-listed pharmaceutical preparations can also contain further pharmaceutical active compounds.
,. :.., -:
The above-listed pharmaceutical preparations are prepared in a customary manner according to known methods, e.g. by mixing the active compound(s) with the excipient(s).

In order to achieve the desired results, it h~s in general been found advantageous both in human and in veterinary medicine to administer the active compound( 8 ) according to the invention in total quantities of about 0.5 to about 500, preferably l to 100~ mg/ky of body weight every 24 hours, optionally in the form of several individual doses. One individual dose prefer.ably contains the compound(~i) in quantities of about 1 to about 80, in particular 1 to 30, mg/kg of body weight. However, it can be necessary to deviate from the ~aid dosages, specifically depending on the nature and the body weight o the subjeat to be treated, the nature and the severity o~ the disease, the type of preparation and of the admini~itration of the phaxmaceutical, as well asi the period or intexval within which the administration takes place.

-: , :

Le A 29_3~25 - 29 ~

~fi~92 Startinq compounds Example I

4-Methyl-2-[2-(3-methylphenyl)ethyl]benzoic acid H3C ~ CH3 2,4-Dimethylbenzoic acid (54 g, 0.36 mol), dissolved in THF (500 ml), is added dropwise, ~etween 10 - 20C, to a solution of LDA (0.76 mol) in THF/n-hexane (1 l/300 ml~. :
The mixture is subsequently stirred ~t RT for 30 mi~ and then cooled to -20C. 3-Methylbenzyl bromide (80 g, 0.43 mol), in THF (300 ml), is added dropwise at this temperature. The mixture is subsequently stirred at the sam2 temperature for 15 min, and worked up. For ~his, the mixture is partitioned between 2 N hydrochloric acid and EtOAc, the aqueous phase is extracted with EtOAc, and the organic phases are combined, wa~hed with saturated NaCl, :~ dried (MgSO4) and concentrated in vacuo. The residue is puri~ied on silica gel using toluene/EtOAc 10:1 as the eluant, and the resulting product i~ crystallised from ether/petroleum: ether. .. -.
: Yield: 45.3:g (42~ of~ heory) 20 ~ lH-NMR (CDC13): ~ ~ .32 (s, 3~; ;2,38 ts, 3H); 2.90 (m, 2H); 3.30 (m, 2H) 7.00 - 7.25 ~m, 6H); 8.00 ~d, J =
; 9 Hz, lH)~
.-,~
Le A 29 325 - 30 -., ,., ,, ,, . ; .,, , , ., . " : . , , :." , , . , :

Example II

2,8-Dimethyl-5-oxo-dibenzo[a,d3cyclohepta-1,4-diene O ~ .

H3C ~ CH3 22.65 g (89 mmol) of the compound fxom Example I are heated in sulpholane (110 g) and polyphosphoric acid (460 g) at 110C for 4 h. After cooling, the solution is poured into water (2 l) and extracted three times with EtOAc, and the combined organic phase~ are washed with water and dried (MgSO4). After evaporation in vacuo, chromatography on silica gel takes place using pure toluene as the eluant and the resulting product is crystalli ed ~rom ether/petroleum ether. .:
Yield: 21.05 g (100% o~ theory) -lH-NMR (CDCl3): ~ - 2.35 (8, 6H), 3.12 (5, 4H); 7-00 (s~ .
2H); 7.12 (d, J = 8 Hz, 2H); 7.98 (d, J = 8 Hz, ~H). :.
.. .. , : ~

~ ;, , .,~
- , ~.:

, ;
~ ~ ~ "~ ,, .
' ,' : ' .
;, ' Le A 29 325 - 31 - :-~ ~''..'' '' 2 1 ~ 2 Example III

2,8-Dimethyl-5-oxo-dibenzo[ a, d]cyclohepta-1,4,6-triene o H3C ~ CH
21 g (88.9 mmol) of the compound from Example II are dissolved in tetrachloromethane (450 ml) and irradiated with N-bromosuccinimide (19 g, 107 mmol) at 55C using a 250 W photographic lamp. After 7 h, the solution is cooled and then ~iltered, the filtrate is concentrated in vacuo and the residue is dissolved in DMF ~70 ml). The solution is heated to 80C and DBN (13.25 g, 107 mmol) i3 added at this temperature. After 15 min, the mixture is cooled and partitioned between water and ether, the aqueous phase is extracted once with ether, and th~
combined organic phases are washed with l N hydrochloric acid (3x) and water (2x), dried (MgS04) and concentrated -in vacuo. ~he residue i8 cry~tallised from ether/petroleum ether. 11.4 g of product are obtained. A
~urther 2.2 y of product can be obtained from the mother liquor by chromatography on silica yel using pure toluene ~ as the eluant.
; ~ 20 Yield: 13.6 g (65% of theory) H-~R ~CDCl3) ~ = 2.46 (~, 6H); 6.95 ~, 2H); 7.32 ~5, 2H); 7.36 (d, J = 8 Hz, 2H); 8~19 ~d, J ~ 8 Hz, 2~).

; '' , .',' .: -.~'. .

Le A 29 325 - 32 -'' 2 ~ Q ~

Exam~le IV :

2,8-Bis-bromomethyl-5-oxo-dibenzo[a,d]cyclohepta-1,4,6- :
triene O .~ " .

Br ~ Br 39.8 g (170 mmol) of the compound from Example III and -N-bromosuccinimide are heated under reflux for about 4 h :
in tetrachloromethane (1.5 l) while being irradiated by .:
a 250 W photographic lamp. The reaction i~ stopped when the desired dibromide can be ~een, by TLC, to be the main - :
component in the mixture of starting compound, mono- `~
bromide, dibromide and by-products. Undi~solved material .~
is filtered off with sustion while hot, washing with :.
tetrachloromethaneO The re~idue is recrystalli~ed from dichloromethane, thereby yielding ~0 g of product which .
r is contaminated with succinimide. The first filtrate and ~-~15 the mother liquor from the crysta:Llisation are combined and concentrated in Yacuo~ :and the re~idue is chromato- :~
graphed on ~ilica gel using~pure toluene as the eluant.
12:g of product and about 17 g of monobromo compound are obtained. This monobromo compound (17 g, 54 mmol) is 20~ reacted preci~ely according to he a~ove instructions ~:.
~ : with N-bromo6uccinimide (11.6 g~ 65 mmol) and a furthe~
: 8.6 g o~ the desired dibromide are obtained.
: : Yield: 40.6 g (65.5%):
'H-NMR (CDCl3):: ~ = 4.56 (s, 4~); 7.03 (s, 2H); 7.53 (9, ,; .
.. . ...

''~'`'"
.'' ,, .

Le A 29 325 - 33 -:.

2H); 7.57 (d, J = 8 Hz, 2H); 8.20 (d, J = 8 Hz, 2H).

Example_V

2,8-Bis-azidomethyl-5-oxo-dibenzo[a,d]cyclohepta-1,4,6-triene O ', N3 ~ N3 36.5 g (93 mmol~ of the compound from Example IV are suspended in DMSO (250 ml) and then mixed at RT with lithium azide (13.7 g, 280 mmol). After about 10 min, the solids are completely dissolved. Working up takes place after 30 min. This is done by partitioning between EtOAc and saturated NaCl, and extracting the aqueous phase wi h EtOAc. The o~ganic phase~ are combined, washed three times with saturated NaCl, dried (MgSO~) and concent-rated, but not quite to dryne~s, in vacuo at RT. The concentrated solution which remains is mixed with petxo-leum ether and the resultant solid (15.15 g) is filtered off with suction. The mother liquor is concentrated and the residue is chromatographed on silica gel using toluene/EtOAc 10:1 as th~ eluant. This yields a further
3.6 g of the title compound.
Yield: 18.75 g (63.5%) 1H-NMR (CDCl3): ~ = 4.50 (s, 6H); 7.08 (s, 2H); 7.48 (m 4H); 8.24 (d, J - 8 ~z~ 2H).
' Le A 29 325 - 34 -. , , . . . : . : . . . , :.. . . :,: .. " .. . . .; , . , : .

~fi~? :: -Exa~ple VI

2,8-Bis-phenylmethoxycarbonylaminomethyl-5-oxo-dibenzo[a,d]cyclohepta-1,4,6-triene O

H5C~H~C-OIC - NH ~ HN - C02-CH~-C6H5 Water (45 ml) and triphenylphosphine (29.5 g, 112.3 mmol) S are added to 18.75 g (51.1 mmol) of the compound from Example V in ~HF (700 ml) and the mixture i8 stirred at RT overnight. For the working up~ the mixture is concentrated in vacuo, taken up in dichloromethane and the aqueous phas~ separated off, and the organic phase is then dried (MgS04), concentrated in vacuo and thoroughly dried under h;gh vacuum. The crude diamine thuæ obtained is dissolved in dichloromethane (l l) and, at -5C, triethylamine (33.3 g, 330 mmol) and benzyloxycarbonyl chloride (3705 g, 220 mmol) are successively added.
Subsequently, the mixture is allowed to reaah RT and is then stirred for 3.5 h. For the working up, the mixture i~ diluted with dichloromethane (1 l), extracted once with water a~d filtered with suction to remove the solid which i~ pre~ent, and the residue i~ then discarded. ~he aqueou~ phase is extracted with dichloromethane and the combined organic phases are washed with saturated Na~CO3, dried (MgSO4) and concen~rated in vacuo ~o about 300 ml.
The re~ulting jelly-like solid is filtered o~ with : . ~uction and the mother liquor i8 concentrated coIpletely :
:
Le_A 29 325 - 35 - ;

: ,...

~ ~fi,~2 and subsequently chromatographed on silica gel using toluene/EtOAc 2:1 as the eluant. The fractions containing the product are concentrated and comhined with the jelly obtained above. This residue is dissolved in hot dichloromethane/methanol 1:1, and EtOAc (200 ml) and toluene t200 ml) are added and the mixture concentrated in vacuo to about 100 ml. During this, solid which is readily filterable precipitates out, and this solid was isolated by filtration.
10 Yield: 11.5 g (42% of theory) H-NMR (DMSO-d6): ~ = 4,39 (d, J = 7 Hz, 4H), 5.00 (s, 4H); 7.10 (s, 2H); 7.30 (m, 10H); 7.45 (d, J = 8 Hz, 2H);
7.51 (s, 2H); 7.91 (t, J = 7 Hz, 2H); 8.03 (d, J = 8 Hz, 2H)-Example VII

2,8-Bis-phenylmethoxycarbonylaminomethyl-10,11-dibxomo-5-oxo-dibenzo[a,d~cyclohepta~1~4-diene O . ' .

H~C6-H2C-o~C~ coz-cHl-c~iH5 Br Br :10 g (18.8 mmol) of the compound ~rom Example VI and ::
bromine ~6g, 38 mmol) are ~tirred overnight in dichloro- :~
~0methane (600 ml) and glacial acetic acid (200 ml) with the exclusion of lightO The mixture i~ then concentrated . .
: in vacuo and the residue is chromatographed on silica gel : ~ .
. .
.:' .' :

Le A 29 325 - 36 -,:: , : : ::. . .. . . .

2:~6~2 ~',.-uslng toluene/EtOAc/formic acid 5:1:0.02. :-Yield: 11.0 g (84.5% of theory) 'H-NMR (DMSO-d6): ~ = 4.30 (d, J = 7Hz, 4H); 5.08 (s, 4H);
6.12 ~s, 2H); 7.35 (m, 12H); 7.95 (m, 4H).

Preparation examples Exam~le 1, Example 2 and Example 3 (tran~)-2,8-Bis-phenylmethoxycarbonylaminomethyl-10,11-diacetoxy-5-oxo-dibenzo[a,d]cyclohepta-1,4-diene : ;

C6EIs 0~ ~ HN O~C6H5 AcO OAc :

. i, (cis)-10-Acetoxy-2,8-bis-phenylmethoxycarbonylamino- ~: .
methyl-11-hydroxy-5-oxo-dibenzo[a,d]cyclohepta-1,4-diene , C6H5 ~ o N ~ HN o ~ C6H5 () AcO OH

; (Ci8 )-11-Acetoxy-5-hydroxy-2,8-bi~-phenylm thoxycarbonyl~

"
;.
, .

Le A 29 325 - 37 -- ; : ,; . ' ,- ', ',, :; . .:: . ::,-' ' . :'; :' : ' 2 ~ 2 aminomethyl-dibenzo[b,e]bicyclo[2.1.3]1-oxaoctane OH

C6H5 o ~ NH ~ HN O ~ C6H5 OAc 2.44 g (3.53 mmol) of the compound from Example VII and silver acetate (1.77 g, 10.6 mmol) are maintained under :
reflux for 3 h in dry acetic acid (100 ml, pxepared by .
heating 150 ml of acetic acid and 10 ml of acetic anhydride under reflux for 1 h). Subsequently, the : .:
: mixture i~ cooled and filtered to remove solid, and the ~:.
filtrate is concentrated in vacuo. The re~idue is : ~ chromatographed on ~ilica gel using toluene/ethyl acetate : lO 2:1 as the eluant. This re~ults ln the elution of the trans compound lExample 1~. Subsequently, the ci8 component ::(Example 2) iq eIuted using ethyl : :
~: acetate/acetone 1~
- ~ .
: ; Example 1 ~15 ~ ~ Yield: 1.57 g (68.5% o~ theory) `~
H-NMR (DMSO-d6): ~ ~ 1.82 (8, 6H); 4.28 (d, J c 7 ~z, :
4~); 5.05 (5, 4H); 6.21 (8~ 2H); 7.35 (m, 14H), 7.82 (d, J -:8 Hz, 2Ht; 7.95 (t, J a 7Hz, 2H~

.;

- : .
..
, .: , ' ~e A 29 325 - 38 - ;
-..

Example 2 Yield: 0.43 g (20% of theory) -.
'H-NMR (DMSO-d6): ~ = 2.02 (s, 3H); 4.29 (d, J = 7 Hz, 4H); 5.06 (m, 5~); 6.12 ts, 1~); 6.19 (d, J = 5 Hz, lH);
7.31 (m, 13H); 7.50 (s, lH); 7.73 (d, J = 8 ~z, lH~; 7.79 (d, J = 8 Hz, lH); 7.96 (t, J = 7 Hz, 2H).

As well as 89% of the compound from Exiample 2, 11% of the compound from ~xample 3, which is in equilibrium with Example 2, is also seen in the lH-NMR. Characteristic algnals: lH-NMR (DMSO-d6~: ~ = 4.10 (d, J = 2 Hz, 2H); . .
4.19 (d, J = 7 Hz, 2H); 5.42 (s, lH); 7.00 - 7.25 ~m, 6H).

Exam~le 4 (trans)-2,8-Bis-phenylmethoxycarbonylaminomethyl-10,11-dihydroxy-5-oxo-dibenzo[a,d]cyclohepta-1,4-diene C6H5--OJ~ r.,~ O~c6Hs ~ ;

HO OH
: 0.1 N NaO~ (126 ml) is added to 1.8 g (2~76 mmol) of the compound from Example 1 in ethanol (180 ml) and the ~.
mixture i~ ~tirred at RT for 1 h. Subsequently, the . :
alcohol is evaporated off in vacuo and the aqueous phase is extracted three time~ with EtOAc. The organic phases are combined, washed with aaturated NaCl, dried (MgSO4) Le A 29 325 ~ 39 -~1 ~6~

and concentrated in vacuo. The residue i5 stirred with dichloromethane, and the resulting solid (1.3~ g) is filtered off with suction. The mother liquor is concentrated and chromatographed on silica gel using tolueneJethyl acetate 1:1, then 1:2, as the eluant. This yields a further 0.18 g of product.
MS (FAB): 567 (M++H, 100%) lH-NMR (DMSO-d6): ~ = 4.26 td, J = 7 Hz, 4H); 4.86 Im, :
2~); 5dOB (s, 4H); 5.82 ~m, 2H~; 7.23 (d, J = 8 ~z, 2~);
7.25 (s, 2H); 7.32 (s, 10~); 7.65 (d, J = 8 ~z, 2H); 7~93 (t, J = 7 Hz, 2H).
As well as 94% of the compound from Example 4, 6% of the i~omeric hemiacetal is also seen in analogy with Example 3 in the 'H-NMR. Characteristic signals~ N~R (DMSO-d6):
~ = 4.10 (d, J = 7 Hz, 2H); 4.17 (dm, J = 7 Hz, 2~); 5.02 (m, lH); 5.22 (d, J = 6 Hz, lH); 5.76 (d, J = 5 Hz, 1~);
7.80 (s, lH, OH).

Example 5 '.:' (cis)-2,8-Bi~-phenylmethoxycarbonylaminomethyl-10,11-dihydroxy-5-oxo-dibenzo[a,d]cyclohepta-1,4-diene C~H5 ~ O ~ ~ ~ ~ HN ~ o ~ C6H
HO ON
The compound is prepared from the compound of Example 2 ~in analogy with the instructions in Example 4.

..
: . ' - .

Le A 29 325 - 40 -, ., ., ,.j.. , ., ~ . . . .. .. .. . .. ... ... .. .. .. . .. . .

~ ~fi~2 Yield: 81%
lH-NMR (DMSO-d6): ~ = 4.28 (d, J = 7 Hz, 4H); 4-89 (d, J
= 6 Hz, 2H); 5.07 (s, 4H); 5.70 (d, J = 6 Hz, 2H); 7.23 (d, J = 8 Hz, 2H); 7.32 (s, 10~); 7.50 (s, 2H); 7.73 (d, J = 8 Hz, 2H); 7.94 (t, J = 7 ~Iz, 2H).
As well as 91% of the compound ~rom Example 4, 9% of the ;:~
isomeric hemiacetal is also seen in analogy with Exilmple 3 in the IH-NMR. Characteristic signals: IH-NMR (DMSO-d6): :
~ = 4.10 (d, J = 7 Hz, 2H); 4.17 (d, J = 7 Hz, 2H); 5.02 (m, lH); 5.28 (s, lH); 7.86 (s, lH, OH).

Example 6 . ~-(trans)-10,11-Dihydroxy-2,8-bis-[5, 5 -dimethyl-4,4-dioxo- :
2-(1-naphthylmethyl)-4-thiahexanoylaminomethyl-5-oxo-dibenzo[a, d] cyclohepta-1,4 -diene (~3C)3C-O~S I ~ SO~-C~CH~
O HO OH O :
:. :

200 mg t0.35 mmol) of the compound from Exiample 4 are ~ -hydrogenated under 1 bar in methanol (100 ml) and in the presence of 1096 Pd/C (40 :mg) for 3.5 h. Sub~equently, the mixture is filtered to remove the cataly~t, and the filtrate i8 concentrated in vacuo. HOB~ (95 mg, :
, .

Le A 29 325 - 41 -'~ ' : , . . .. . . . . .

,, . ,, ' . ' , , ,; ... ' .. . . -, ' '' , ' :~ .

~ ~ Q ~ 3 O.70 mmol) and DCC (160 mg, 0.78 mmol) are added to 5,5-dimethyl-4,4-dioxo-2-(1-naphthylmethyl)-4-thiahexanoic acid (235 mg, 0~70 mmol) in THF (4 ml), while cooling with ice. The mixture is subsequently stirred at RT for 1 h and then added to the crude diamine (obtained above by hydrogenation) in dichloromethane (2 ml3. The mixture is subsequently stirred at RT for 5 h and then diluted with EtOAc (150 ml). The solution is washed with 4%
strength acetic acid (25 ml), saturated Na~CO3, and saturated NaCl, and then dried (MgSOs) and concentrated in vacuo. The residue is purified on ~ilica gel u~ing EtOAc/acetone 5:1, and then 5:2. A jelly-like product i~
obtained which i8 thoroughly triturated with dichloro-methane to achieve crystallisation. Further product can be obtained from the mother liquor by dissolving in acetone/methanol, adding ether and crystalli~ing in a refrigerator.
Yield: 46 mg (14% o~ theory) ~ :
lH-NMR ~DMSO-d6): ~ = 1,24 (s, 9H~; 3.10 (dd, J = 14 Hz and 3 Hz, 2~); 3.35 (m, 6H); 3.59 (dd, J = 14 Hz and 6 Hz, 2H); 4.16 (dd, J = 16 and 5 Hz, 2H); 4.30 (dd, J = ~ -16 Hz and 5 Hz, 2H), 4.82 (m, 2H); 5.71 ~m, 2~); 6.88 (d, J = 8 Hz, 2H); 7.21 (s, 2H); 7.30 - 7.S0 (m, 10H), 7.83 (d, J = 8 Hz, 2H); 7.95 (d, J = 8 ~z, 2~); 8.24 (d, J ~
7 Hz, 2Ht; 8.64 (t, J = 5 Hz, 2H)~
.:
The compound~ listed in Table 1 are prepared in analogy with the lnatructions in Ex~sple 6:

, ~ ~ ''"

~ ~' ''.

Le A 29 325 - 42 ~
' :

:, .. . , . , . . , . . " ." ~ . .... ......... .. . . . .. .. . . .. . .. ..

Table 1: ;

R,-OGHN-H2C ~cHz-NH-co-F(2 HO OH ~ .

Esample ~' R1 ~2 Yl~ld 7 O\ N- (CH2)2N~O~ O/~ S
CH3 CH3 :
' ~, 8 (~ 5 9 ~ 32 , Exam~le 11 ~trans)-10,11-Bis-(tert-butyldimethylsilyloxy)-2,8-bi~-phenylmethoxycarbony}aminomethyl-5-oxo-dibenzo[a,d]cy~lo-hepta-1,4-diene :

C6H5--oJ~ r} ~J~O~C6H5 (H3C)3C~C)2-SiO OSi-(CH3)2~(CH3)3 ~.
: ~ Imidazole (1.9 g, 28.4 mmol) and ~er~-butyldimethylsilyl . ~ .
:.', ~':

Le A 29 325 - 43 ~

,~ ,, ,, , . . : , ........... . ..
. , : ' ', ', .~, ' ' . ' . ' , ' . '',' , ,,, ' ,, , . ' .; ' ,. .' ' ~ .
: : .. : ~ .: . , , -chloride (2.35 g, 15.6 mmol) are added at RT to 4 g (7.1 mmol) of the compound from Example 4 and the mixture is then stirred at 50C for 2.5 h. For the working up, the mixture is diluted with EtOAc, washed with watex, twice with 1 N hydrochloric acid and then with saturated NaC1, and subsequently dried (MgSO~) and concentrated in vacuo. The residue is purified on silica gel using toluene/EtOAc 10:1 as the eluant. .
Yield: 5.1 g (90.5% of theory) IH-NMR (CDCl3)o ~ = 0.19 (s, 6H), 0.07 (s, 6H); 0.61 (s, : .
18H), 4.42 (d, J = 6 Hz, 4H); 4.93 (s, 2H); 5.04 (t, br, :
J = 6 Hz, 2H); S.15 (s, 4H); 7.15 (s, 2H); 7.24 (m, 2H); :
7.35 (m, 10H); ~.89 (d, J = 8 Hz, 2H).

Example 12 (trans)-10,11-Dihydroxy-2,8-bis-[methyl(phenylmethoxy-carbonyl)amino]methyl-5-oxo-dibenzo[a,d]cyclohepta-1,4,6-triene :
O :.~, C6~5 ~ 0 ~ N ~ I C~H5 CH3 OH CH3 :.

A 35% potassium hydride suspension (11.3 mg, 0.283 mmol) : and methyl iodide (48 mg, 0.34 mmol) a~e added to 90 mg .
(0.113 ~mmol) of: the compound from Example 11 in DMF . :
(9 ml), while cooling with ice. After 15 min at the ~ame ~.
temperature, working up is carri~d out. The mixture is ~ ,''i '.

.; . .

Le A 29 325 ~ 44 - ;
.

''' ;",', ,":,''' ~,','' ' '; 'i' ~ "'"''' " '','' '.'''", ' '''"'','',' '''-partitioned between EtOAc and 1 N hydrochloric acid, theaqueous phase is extracted with EtOAc, and the combined organic phases are then washed with saturated NaC1, dried (MgSO4) and concentrated in vacuo. The residue is `
purified on silica gel using toluene/EtOAc 10:1 as the eluant. 48 mg of an intermediate are obtained whose silyl protective groups are removed in accordance with a general method for removing silyl sroups (n-Bu4NF, THF, RT).
Yield- 22 mg (33% of theory) -`
H-NMR (CDC13): ~ = 3.86 and 3.92 (2s, 6H), 4.52 (s, 4H);
4.90 (br, 2H); 5.17 (s, 4H); 7.20 - 7.40 (m, 14H); 7.46 and 7.58 (2br, 2H); 7.84 (d, J = 8 Hz, 2H).

.

Le A 29 325 - 45 - .
. ', . '

Claims (16)

  1. Patent claims l. 5-Oxo-dibenzo[a,d]cyclohepta-1,4-dienes of the general formula ( I ) in which R1 and R3 are identical or different and represent an amino-protective group or represent a group of the formula R7-Co-, in which R7 denotes hydrogen, trifluoromethyl, or straight-chain or branched alkoxy having up to 8 carbon atoms or alkyl having up to 18 carbon atoms, which are optionally substituted identically or differently up to 2 times by aryl : having 6 to 10 carbon atoms or pyridyl, or denotes aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, trifluoromethyl, tri-fluoromethoxy, or by straight-chain or branched alkyl having up to 8 carbon atoms, denotes cycloalkyl having 3 to 7 carbon atoms, or denotes quinolyl, quinolyl N oxide, indolyl, pyridyl, morpholino or piperazinyl, or denotes a residue of the formula Rg-Y-CH2-CH- ' R10-CO-O-CH-R11-S(O)m-NH-CH- ' T-NH-(CH12)p-or R12-P-(CH2)s-CH
    in which R8 denotes phenyl or naphthyl, . R9, R10 and R11, independently of each other, denote straight-chain or branched alkyl having up to 14 carbon atoms, which is option-ally substituted by phenyl or naphthyl, or denote aryl having *
    6 to 10 carbon atoms, which for its part is substituted by alkyl having up to 4 carbon atoms, or R10 denotes a residue of the formula m denotes a number 0, 1 or 2, T denotes morpholino or cyclohexyl, p denotes a number 1, 2 or 3, Y and Y', independently of each other, represent CO- or SO2-, t denotes a number 0 or 1, R12 and R13, independently of each other, represent hydroxyl or alkoxy having up to 8 carbon atoms, s represents a number 1 or 2, R2 and R4 are identical or different and represent hydrogen, or straight-chain or branched alkyl having up to 8 carbon atom, R5 and R6 are identical or different and represent hydrogen, or represent straight-chain or branched acyl or alkoxycarbonyl having in each case up to 8 carbon atoms, or represent a hydroxyl-protective group, and in the case that either R5 or R6 represents hydrogen, in the form of their hemiacetals and s its thereof.
  2. 2. Compounds of general formula (I) according to Claim 1, in which R1 and R3 are identical or different and represent benzyloxycarbonyl, 4-methoxybenzyloxy-carbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-nitrobenzyloxycarbonyl, fluorenyl-9-methoxycarbonyl or 2,2,2-trifluoroacetyl, or represent a group of the formula R7-Co-, R7 denotes hydrogen, trifluoromethyl, or straight-chain or branched alkoxy having up to 4 carbon atoms or alkyl having up to 16 carbon atoms, which are optionally substituted identically or differently up to 2 times by phenyl, naphthyl or pyridyl, or denotes phenyl or naphthyl, which can be optionally substituted by fluorine, chlorine, trifluoromethyl, trifluoro-methoxy, or by straight-chain or hranched alkyl having up to 6 carbon atoms, denotes cyclopropyl, cyclopentyl, cyclo-hexyl, quinolyl, quinolyl N-oxide, indolyl, pyridyl, morpholino or piperazinyl, or denotes a residue of the formula or Y denotes the CO or SO2 group, R9 denotes phenyl or naphthyl, R9, R10 and R11, independently of each other, represent straight-chain or branched alkyl having up to 8 carbon atoms, tolyl, phenyl or naphthyl, or R10 denotes a residue of the formula m denotes a number 1 or 2, R2 and R4 are identical or different and represent hydrogen, or straight-chain or branched alkyl having up to 6 carbon atoms, R5 and R6 are identical or different and represent hydrogen, or represent straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms or represent trimethylsilyl, triethylsilyl, triisopropylsilyl,tert-butyl-dimethylsilyl, triphenylsilyl, benzyloxycarbonyl, 4-nitro-benzyloxycarbonyl, tert-butoxycarbonyl, a l l y l o x y c a r b o n y l , 4 - m e t h o x y-benzyloxycarbonyl, formyl, acetyl or tri-chloroacetyl, and in the case that either R5 or R6 represents hydrogen, in the form of their hemiacetals and salts thereof.
  3. 3. Compounds of the general formula (I) according to Claim 1, in which R2 and R3 are identical or different and represent benzyloxycarbonyl, 4-methoxybenzyloxy-carbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-nitrobenzyloxycarbonyl, fluorenyl-9-methoxycarbonyl or 2,2,2-trifluoroacetyl, or represent a group of the formula R7-Co-in which R7 denotes hydrogen, trifluoromethyl, or straight-chain or branched alkoxy having up to 4 and alkyl having up to 14 carbon atoms, which are optionally substituted up to 2 times by phenyl, naphthyl or pyridyl, or denotes phenyl or naphthyl, which can optionally be substituted by fluorine, chlorine, trifluoxomethyl, trifluoro-methoxy, or by straight-chain or branched alkyl having up to 4 carbon atoms, denotes cyclopropyl, cyclopentyl, cyclo-hexyl, quinolyl, quinolyl N-oxide, indolyl, pyridyl, morpholino or piperazinyl, or denotes a residue of the formula or in which Y denotes the CO or SO2 group, R8 denotes phenyl or naphthyl R9 and R10, independently of each other, represent straight-chain or branched alkyl having up to 4 carbon atoms, tolyl, phenyl or naphthyl, R10 represents a residue of the formula, R2 and R4 are identical or different and represent hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms, Rs and R6 are identical or different and represent hydrogen, or represent straight-chain or branahed acyl or alkoxycarbonyl having in each case up to 4 carbon atoms, or represent trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl, triphenylsilyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbony allyloxycarbonyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl or trichloroacetyl, and in the case that either R5 or R6 represent hydrogen, in the form of their hemiacetals and salts thereof.
  4. 4. The compound (trans)-2,8-bis-phenylmethoxycarbonyl-aminomethyl-10,11-dihydroxy-5-oxo-dibenzo[a,d]cyclohepta-1,4-diene or the hemiacetal thereof.
  5. 5. The compound (cis)-2,8-bis-phenylmethoxycarbonyl-aminomethyl-10,11-dihydroxy-5-oxo-dibenzo[a,d]cyclohepta-1,4-diene or the hemiacetal thereof.
  6. 6. The compound (trans)-10,11-dihydroxy-2,8-bis-[5,5-dimethyl-4,4-dioxo-2-(1-naphthylmethyl)-4-thiahexanoylamino-ethyl-5-oxo-dibenzo[a,d]cyclohepta-1,4-diene.
  7. 7. A process for preparing a compound of the general formula (I) accord to claim 1, characterised in that a compound of the general formula (III) (III), in which X is a leaving group, R14 and R15 are identical or different and represent an amino-protective group, is reacted with a carboxylic acid of the general formula (IV) R16-CO2H (IV) in which R16 includes the respective range of meaning listed above for the substituents R5 and R6, with the exception of hydrogen, and in the presence of a corresponding salt, into the compounds of the general formulae (Ia) and Ib) (Ia) (Ib) in which R14 and R15 have the above-mentioned meaning, R16 likewise has the above-mentioned meaning, the hydroxyl function (R5/R6=H) is subsequently liberated by hydrolysis, and if there is required a compound of formula (I) in which R1 and R have values other than the amino-protective radicals R14 and R15, the radicals R14 and R15 are eliminated to liberate the amino function, and are reacted with a compound of the general formula (V) R17-CO2H (V) in which R17 embraces the range of meaning of the above-listed substituents R1 and R3, in inert solvents, in the presence of a base and/or of an auxiliary compound, optionally with prior activation of the carboxylic acid function.
  8. 8. A process according to claim 7, wherein the groups R14 and R15 are both phenylmethoxycarbonyl groups and the corresponding salt is the silver salt of the acid R16-CO2H.
  9. 9. A process according to claim 7, wherein R16-CO is the acetyl group and the corresponding salt is silver acetate.
  10. 10. A process according to claim 7, wherein the compound of the general formula (III) is obtained by reacting a compound of the general formula in which R14 and R15 are as defined in claim 7, with elemental bromine.
  11. 11. A compound of the general formula (Ia) or (Ib) as defined in claim 7.
  12. 12. A compound of the general formula (III) as defined in claim 7.
  13. 13. A pharmaceutical composition which comprises a compound of the general formula (I), according to any one of claims 1 to 7, or a hemiacetal or a pharmaceutically acceptable salt thereof, together with a suitable diluent or carrier.
  14. 14. A process for preparing a pharmaceutical composition for use in combating retroviruses, which process comprises admixing a compound of the general formula (I), according to any one of claims 1 to 7, or a hemiacetal or a pharmaceutically acceptable salt thereof, with a suitable diluent or carrier.
  15. 15. Use of a compound of the general formula (I), according to any one of claims 1 to 7, or a hemiacetal or a pharma-ceutically acceptable salt thereof, for combating retroviruses.
  16. 16. A commercial package containing, as active pharma-ceutical ingredient, a compound of the general formula (I), according to any one of claims 1 to 7, or a hemiacetal or a pharmaceutically acceptable salt thereof, together with instructions for its use for combating retroviruses.
CA002106892A 1992-09-25 1993-09-24 5-oxo-dibenzo(a,d)cyclohepta-1,4-dienes Abandoned CA2106892A1 (en)

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US6071895A (en) 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
RU2126794C1 (en) 1992-03-11 1999-02-27 Нархекс Лимитед Amino-derivatives of oxo- or hydroxy-substituted hydrazines, method of their synthesis and pharmaceutical compositions for inhibition of retrovirus protease
US5888992A (en) 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
US5705524A (en) * 1994-11-04 1998-01-06 Gilead Sciences, Inc. Thiepane compounds
US6034118A (en) * 1994-11-04 2000-03-07 Gilead Sciences, Inc. Thiepane compounds
US6169911B1 (en) 1997-09-26 2001-01-02 Sun Microsystems, Inc. Graphical user interface for a portable telephone
US6313110B1 (en) 1999-06-02 2001-11-06 Dupont Pharmaceuticals Company Substituted 2H-1,3-diazapin-2-one useful as an HIV protease inhibitor
DE10238818A1 (en) 2002-08-23 2004-03-04 Wacker-Chemie Gmbh Organosilicon compounds containing cyclodextrin residues
CN106414392B (en) * 2014-06-10 2019-05-14 华东理工大学 6,7,8,9- tetrahydro -5H- benzo [7] annulene -2- alkyl amine compound and application thereof

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