AU678815B2 - Substituted piperazines - Google Patents

Description

Our Ref: 504310 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STAN~DARD PATENT

S

S

SO

S

*5*S S

S

*S5* 5* S S Applicant(s): Bayer Aktiengesellschaft D-51368 LEVERKUSEN

GERMANY

Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 7'000 Substituted piperazines The following statement is a full description of this invention, including the best method of performing it known to me;- 5020 The invention relates to substituted piperazines, processes for their preparation and their use as antiretroviral agents.

The publication WO 92/024 87-A (JP 3002-144 A) discloses ethylenediamine derivatives having a CNS action. Diarylalkyl-substituted alkylamines having a cardiovascular and cerebrovascular action are additionally described in EP 0229 623. The compounds according to the invention are partially included by the scope of meaning of this publication if R 5

H.

o The present invention relates to substituted piperazines of the general formula (I)

R

1

R

5

R

7 R6- R2 R CHff-- N N (CH2)3- C R C (I)

R

3

R

4 R9 in which

RI,R

2 and R 4 are identical or different and represent 15 hydrogen, nitro, halogen, carboxyl, hydroxyl, formyl, straight-chain or branched alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, trifiuoromethyl, phenyl or represent straight-chain or branched alkyl having up Le A 29 651 1 to 8 carbon atoms, which is optionally substituted by hydroxyl or protected hydroxyl, or represent a group of the formula -NRIR1 1 or -CO-A, in which

R

10 and R 1 are identical or different and denote hydrogen, phenyl, benzyl, an amino protective group or straight-chain or branched alkyl having up to 8 carbon atoms, or e*

R

10 and R 1 together with the nitrogen atom, form a to 7-membered, saturated heterocycle, A denotes the abovementioned group -NR 0

R

11 or the radical of the formula

R

13

-NR

12

(CH

2 a-COR 4 in which 15 R 10 and R' have the abovementioned meaning,

R

12 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, Le A 29 651 2 R" denotes cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms or hydrogen, or denotes straight-chain or branched alkyl having up to 8 carbon atoms, where the alkyl is optionally substituted by methylthio, hydroxyl, mercapto, guanidyl or by a group of the formula -NR"R" 6 or

R

1 7

-OC-,

10 in which

R

s and R" independently of one another denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, 15 and

R

17 denotes hydroxyl, benzyloxy, alkoxy having up to 6 carbon atoms or the abovementioned group -NR'SR", in which

R'

1 and R

I

have the abovementioned meaning, or the alkyl is optionally substituted by Le A 29 651 3 cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which for its part is substituted by hydroxyl, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group -NRi'R 6 in which

R

15 and R 16 have the abovementioned meaning, or the alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or 10 indolyl, in which the corresponding -NH functions are optionally protected by alkyl having up to 6 carbon atoms or by an amino protective group, 15 and a denotes the number 0 or 1,

R

14 denotes hydroxyl or straight-chain or branched alkoxy having up to 8 carbon atoms, *oo or

R

2 and R 3 or R 3 and R 4 together form, including the phenyl double bond;a partially unsaturated Le A 29 651 4 to 7-membered carbocycle,

R

5 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or represents a group of the formula -C0,R 18 in which R" denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or a hydroxyl protective group, or 10 R 5 represents a group of the formula -CO-B, in which B has the abovementioned meaning of A and is identical to or different from this, •.or R' and R 5 including the oxygen atom and the phenyl ring, together form a 5- to 6-membered, unsaturated heterocycle,

R

6 and R' are identical or different and represent hydrogen, carboxyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally Le A 29 651 5 substituted by hydroxyl or phenyl, or represent straight-chain or branched alkoxycarbonyl having up to 8 carbon atoms,

R

8 and R 9 are identical or different and represent halogen, cyano, nitro, azido or hydroxyl, and their salts.

Physiologically acceptable salts of the substituted piperazines can be salts of the substances according to the invention with mineral acids, carboxylic acids or 10 sulphonic acids. Particularly preferred salts, for example, are those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts which may be mentioned are those with customary bases, such as, for example, alkali metal salts (e.g.

sodium or potassium salts), alkaline earth metal salts calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methyl-piperidine.

The compounds according to the invention can exist in Le A 29 651 6 sterecisomeric f orms, which either behave as image and mirz or image (enantiomers) or which do not behave as je and mirror image (diastereomers) The invention relattes both to the antipodes and the racemic f orms and also to the diastereomer mixtures. Like the diastereomers, the racernic forms can be resolved in a known manner into the stereoisomerically uniform constituents [cf.

E.L. Eliel, Stereochemistry of Carbon Compounds, McGi~aw Hill, 1962).

Amino protective groups in the context of the invention are the customary amino protective groups used in peptide chemistry. These preferably include: **obenzyloxycarbonyl, tert-butoxycarbony. and too*%allyloxycarbonyl.

Hydroxyl protective group in general represents trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, benzyll benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, acetyl or tetrahydropyranyl. Trimethylsilyll triethylsilyl, triisopropylsilyl I tert-buty.-dimethy.oilyl, .*..*triphenylsilyl, benzyloxycarbonyl, tert-butoxycarbonyl, o0 allyloxycarbonyl and acetyl are preferred.

Preferred compounds of-the general formula are those in which

RI,R

2 1 Rl and RI are identical or different and represent Le A 29 651,-7 7 hydrogen, nitro, fluorine, chlorine, bromine, carboxyl, hydroxyl, formyl, straight-chain or branched alkoxy or alkoxycarbony. in each case having up to 6 carbon atoms, trifluoronmethyl, phenyl.

or represent straight-chain or branched alkyl h oing up to 6 carbon atoms, which is optionally si~bs Lituted by hydroxyl or protected hydlroxyl, or represent a group of the formula -NR 1 0

R

1 or -CO-A, in which S RIO and R' 1 are identical or different and denote hydrogen, phenyl, benzyloxycarbonyl, butyl, tertbutoxycarbonyl (HOC) acetyl, benzyl or straightchain or branched alkyl having up to 6 carbon atoms, or RIO and together with the nitrogen atom, form a pyrro7,Iidine or piperidine ring, A denotes the abovementioned group -N'OI or th G radical of the formula

(CH

2 )aC0R 14 in which Ir.e -A 29 65.1- 8

R

10 and R" have the abovementioned meaning,

R

1 denotes hydrogen, methyl or ethyl,

R

1 denotes cyclopentyl, cyclohexyl, phenyl or hydrogen, or denotes straight-chain or branched alkyl having up to 6 carbon atoms, where the alkyl can optionally be substituted by methylthio, hydroxyl, mercapto, guanidyl, amino, carboxyl or H 2

N-CO-,

10 or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which for its part can be substituted by fluorine, hydroxyl, nitro or alkoxy having up to 4 carbon atoms, or the alkyl is substituted by indolyl, imidazol- 15 yl, pyridyl, triazolyl or pyrazolyl, where the corresponding -NH functions are optionally protected by alkyl having up to 4 carbon atoms or by an amino protective group,

R"

4 denotes hydroxyl or straight-chain or 20 branched alkoxy having up to 6 carbon atoms, a denotes the number 0 or 1, or Le A 29 651 9 RI and R 3 or R 3 and R 4 in each case together, including the phenyl double bond, form a cyclohexenyl ring,

R

5 represents hvrrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or represents a group of the formula -C0 2

R

B

in which R" denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, acetyl or benzyl, S 10 or

R

5 represents a group of the formula -CO-B, in which B has the abovementioned meaning of A and is identical to or different from this, 15 or 4* o** R' and R 5 including the oxygen atom and the phenyl ring, together form a chroman ring, R' and R 7 are identical or different and represent hydrogen, carboxyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or phenyl, or 2e A--29_SS 10

M

represent straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms,

R

8 and R 9 are identical or different and represent fluorine, chlorine, cyano, nitro, azido or hydroxyl, and their salts.

Particularly preferred compounds of the general formula are those in which *0 *0o R R,R 2

,R

3 and R 4 are identical or different and represent 10 hydrogen, nitro, fluorine, chlorine, bromine, carboxyl, hydroxyl, formyl, straight-chain or branched alkoxy or alkoxycarbonyl in each case having up to 4 carbon atoms, trifluoromethyl, phenyl or *00* 15 represent straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, or represent a group of the formula -NR 0 R" or -CO-A, in which

R

i0 and R 1 are identical or different and denote hydrogen, phenyl, benzyl, benzyloxycarbonyl, butyl, tert-butoxycarbonyl (BOC), acetyl or straight-chain or branched alkyl having up to Le A 29 651 11 4 carbon atoms, or RIO and It", together with the nitrogen atom, f orm a pyrrolidine or piperidine ring, A denotes the abovementioned group -NR' 0

R

1 or the radical of the forxnul.-

R

13

*NR

12

(CH

2 )a-C0R 1 4 ~:in which RIO and R 1 have the abovementioned meaning,

R

12 denotes hydrogen, methyl or ethyl, 10 R" 3 denotes oyclopentyl, cyclohexyl, phenyl or hydrogen, or denotes straight-chain or branched alkyl a 0 having up to 4 carbon atoms, where the alkyl can be optionally substituted by 15 methylthio, hydroxyl, mercapto, guanidyl, amino, carboxyl or fl 2

N-CO-,

or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which for its part can be Le A 29 651 12 substituted by fluorine, hydroxyl, nitro or alkoxy having up to 4 carbon atoms, or the alkyl is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, where the corresponding -NH functions are optionally protected by alkyl having up to 4 carbon atoms or by an amino protective group,

R

1 denotes hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, te 10 a denotes the number 0 or 1, Or or 90

R

2 and R 3 or R 3 and R 4 in each case together, including the phenyl double bond, form a cyclohexenyl ring,

R

5 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or represents a group of the formula -CO 2

R

I

in which

R

18 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, acetyl or benzyl, or Le A 29 651 13 represents a group of the formula -CO-B, in which B has the abovementioned meaning of A and is identical to or different from this, or

R

1 and R 5 including the oxygen atom and the phenyl ring, together form a chroman ring,

R

6 and R 7 are identical or different and represent hydrogen, carboxyl or straight-chain or branched alkyl 10 having up to 4 carbon atoms, which is optionally substituted by hydroxyl or phenyl, or represent straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms,

R

8 and R 9 are identical or different and represent fluorine, chlorine, cyano, nitro or hydroxyl, and their salts.

0** Processes for the preparation of the compounds of the general formula according to the invention have additionally been found, characterized in that compounds of the general formula (II) Le A 29 651 14 R,

R

R

2 I O-CH-CO 2 H (I R3a

R

4 in which R 3 R' and R 5 have the abovementioned meaning, are first converted by reaction with compounds of the general formula (III)

NXR

5

R

7

R

H N- (CH 2 3

-C

in which

R',R

7 R' and RI have the abovementioned meaning, in inert solvents, in the presence of a base and/or 0**o auxiliary, if appropriate with prior activation of the carboxylic acid function, into the compounds of the general formula (IV) Le A 29 651 -115

R

1

R

5

R

6

R

7

R

R

2 RA 0 C O N V N

(CH

2 3 C iN

(IV)R

in which RI rR 2 FR 3

R'R

5

,R

6 ,R',R1 and R' have the abovementioned meaning, and in a second step the carbonyl function is reduced 5 according to customary methods, or compounds of the general formula (V) R, R R 6

R

7 R2 CH-- N/ H (V)

R

3 R 4 in which

R',R

2 1

R',R

4

,R

5 1 R' and R" have the abovementioned meaning, are f irst converted by reaction with compoinds of the general formula (VI) Le A 29 651 16 H0 2 C (OH 2 2

C(I

R

9 in which R'9 and RI have the abovementioied meaning, in inert solvents, if appropriate in the presence of a base and/or auxiliary, into the compounds of the general 5 formula (VII) *eceR 6

R

7 RG 0 RI lt-eu- 2 "2J ~(VII)

:.R

3 R 4 X\

R

in which 1 ,r R 2 j R 3 I R 4

R

5 f, R R 7 R8 and R9 have the abovementioned meaning, and the carbonyl funrvtion is then reduced, or compounds of the general formula (VIII) Le A 29 651 1 V R 6 R 7 R 8 HN N CO--(CH 2 2 Ci (VI I)

R

9 in which R6,R',Re and R 9 have the abovementioned meaning, are first converted by reaction with compounds of the general formula as described in into the 5 compounds of the general formula (IX)

R

7

R

8

R

2 CO N N- CO- (C)

R

3 R 4 in which S" R 1 RI R R R R R and R' have the abovementioned meaning, and the carbonyl function is then reduced, or compounds of the general formula (X) Le A 29 651 18

I

R, RO N

R

2 N N-L (X)

R

3 R 4 in which

R

1

R'

2

,R

3

,R

4

,R

5 and R 7 have the abovementioned meaning and L represents an amino protective group, preferably benzyl, are first reacted, after removal of the amino protective group, with compounds of the general formula (VI) in inert solvents, if appropriate in the presence of a base and/or auxiliary, and a reduction of the carbonyl func- 10 tion is then carried out as described in Is. 0 and in the case of the free carboxylic acids, the respective ester is hydrolysed or saponified with acids or bases, and in the case of an amino acid group, this is prepared 15 according to those methods customary in peptide chemistry, for example by activation of the carboxylic acid function, blocking and deblocking of the corresponding carboxylic acid and/or amino acid functions and condensation, Le A 29 651 19 and in the case of the substituents R1, R 2

R

3 1 R 4 ,1 R 5 1 R 6 1

R

7 r RG and R 9 these are varied according to known processes, f or example by reduction, .Ilkylation or saponification.

The processes according to the invention can be clarified by way of example by the following reaction scheme:

[A)

F

F

0\ O'C02H H_

FF

FF

DCC, HQBT

N

9 *0 *0 9 000 0 0 *000 0000 0000 0* 0* 0

BH

3 xTHF mm- Le A 29 651 20

(B]

H4,C F o N N DCC. HOBT e. S S S 5* 0@

S

5* 5 9 S S

S

BH x THF Le A 29 65].

21

(C]

HN N H3 DCC, HOBT F Q 0 2

H

F

I

e 1 II S S 5050 *5 S S

S

S

S S

BH

3 x THF

F

e -2 9_65 1 22 0 F 01-..N/ThNH -Ct~ Pd-C, NH 4 0 2

CH

H02 44 a 4* a, .4 a a *4 a a *4 a a DCC, HOBT a 4* 3~4 4* a

BH

3

*THF

ci~- f-v be A-69- 23 Suitable solvents are the customary inert solvents which do not cha~nge under the reaction conditions. These preferably include organic solvents such as ethers, e.g.

diethyl ether, glycol mconomethyl ether or glycol dimethyl ether, dioxane or tetrahyvlrofuran, or hydrocarbons such as benzenep toluene, xylene, cyclohexane or mineral oil fractions or halogenohydrocarbons such as dichicromethane, chloroform, carbon tetrachloride, or dimethyl suiphoxide, -limethylformamide, hexamethyiphosphoramide, ethyl acetate, pyridine, triethylamine or picoline. it is also possible to use zniires of the solvents mentioned.

'*.:Dichioromethane, chloroform, dimethylformamide or tetrahydrofuran are particularly preferred.

0* S bases. These preferably inilude alkali metal hyeioxides such as, for example, lithiun, hydroxide, 6odiun hydroxido 0:0*or potatsium hydroxidet alkaline earth metal hydroxidei $0400 such as, for example, bariuA hydroxide, alkali metal carbonates such as sodium carbonate or potassium carboo.- *0 ate, alkali metal or alkaline earth metal carbonates, such as calcium carbonate or caesium carbonate, or alkali metal or alkaline earth metal alkoxides or amides such as 4* sodium methoxide or potassium methoxide, sodium ethoxide.

or potassium ethoxide or potassium tert-butoxide, or lithium diisopropyl.amide (LDA), or organic amnines (trialkyl(CI-C6)amines) such as triethylamine, or heterocycles such as 1, 4-diazabicyclo[ 2. 2.2 joctane (DABCO),1 1, 8-diazabi- 0]undec-7-ene (DBU), pyridie, diaminopyridine, 2k, methylpiperidine or morpholine. As bases, it is also possible to employ alkali metals, such as sodium, or their hydrides such as sodium hydride. Potassium carbonate, sodium hydride, potassium tert-butoxide or caesium carbonate is preferred.

In general, the base is employed in an amount from 0.05 mol to 10 mol, preferably from 1 mol to 2 mol, in each case relative to 1 mol of the compounds of the formulae (III), and (VIII).

10 The processes according to the invention are in general carried out in a temperature range from -100 0 C to +100*C, preferably from 0°C to The processes according to the invention are in general carried out at normal pressure. However, it is also possible to carry out the processes at elevated pressure or at rc -ced pressure (e.g in a range from 0.5 to 5 bar).

Auxiliaries employed are preferably condensing agents, which can also be bases, in particular if the carboxyl group is present in activated form as an anhydride. The customary condensing agents such as carbodiimides, e.g.

N,N'-diethyl-, N,N'-diisopropyl- and N,N'-dicyclohexylcarbodiimidef N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride, N-cyclohexyl-N'-(2morpholinoethyl) -carbodiimide metho-p-toluenesulphonate, or carbonyl compounds such as carbonyldiimidazole, or Le A 29 651 25 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2oxazolium-3-sulphate or perchlorate, or acylamino compounds such as 2-ethoxy-lethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or benzotriazolyloxytris(dimethylamino phosphonium hexafluorophosphate or 1-hydroxybenzotriazole are preferred here.

Additionally, for example, alkali metal carbonates, e.g.

sodium carbonate or potassium carbonate or sodium hydrogen carbonate or potassium hydrogen carbonate, or organic bases such as trialkylamines, e.g. triethylamine, ethyldiisopropylamine, N-ethylmorpholine, N-methylpiperidine or N-methylmorpholine can be employed. N-methylmorpholine 0 is preferred.

The auxiliaries are employed in an amount from 1.0 mol to mol, preferably 1.0 to 1.2 mol, in each case relative to 1 mol of the compounds of the general formulae (III), (VI) and (VIII).

The reactions are carried out in a temperature range from 20 -30 0 C to 100 0 C, preferably at 0°C to 30 0 C, and at normal pressure.

0* 9 Suitable solvents for the saponification are water or the organic solvents customary for a saponification. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or Le A 29 651 26

I

dimethyl sulphoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used.

It is also possible to employ mixtures of the solvents mentioned.

The saponification is in general carried out in a temperature range from 0 C to +100°C, preferably from +20°C to 0

C.

In general, the saponification is carried out at normal pressure. However, it is also possible to work at reduced 10 pressure or at elevated pressure from 0.5 to 5 bar).

S

When carrying out the saponification, the base is in .general employed in an amount from 1 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 mol of the ester. Molar amounts of the reactants are particularly preferably used.

g** The hydrolysis of tert-butyl esters is in general carried out using acids, such as, for example, hydrochloric acid or trifluoroacetic acid, in the presence of one of the abovementioned solvents and/or water or their mixtures, preferably using dioxane, tetrahydrofuran or dichloromethane.

Suitable solvents for the peptide coupling are the customary organic solvents which do not change under thu reaction conditions. These preferably include organic Le A 29 651 27

-I

solvents such as alcohols, e.g. methanol, ethanol or n-propanol, ethers, e.g. diethyl ether, glycol monomethyl ether or glycol dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or mineral oil fractions or halogenohydrocarbons such as dichloromethane, dichloroethane (DCE), chloroform or carbon tetrachloride, or dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned.

Dichloromethane, dichloroethane, dimethylformamide or n-propanol are particularly preferred.

As auxiliaries for the respective peptide couplings, condensing agents are preferably employed which cn also 15 be bases, in particular if the carboxyl group is present in activated form as an anhydride. Preferably, the customary condensing agents such as carbodiimides, e.g.

N,N'-diethyl-, NN'-dipropyl-, N,N'-diisopropyl- or N,N'dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)- N'-ethylcarbodiimide hydrochloride, or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or 2perchlorate, or acylamino .o compounds such as 2-ethoxy-l-ethoxycarbonyl-1,2-dihydro- 25 quinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or 1-hydroxybenzotriazole and, as bases, alkali metal carbonates, e.g. sodium carbonate or potassium carbonate, sodium hydrogen Le A 29 651 28 carbonate or potassium hydrogen carbonate, or organic bases such as trialkylamines, e.g. triethylamine, Nethylmorpholine, N-methylpiperidine or diisopropylethylamine are employed here. Dicyclohexylcarbodiimide, N-methylmorpholine and 1-hydroxybenzotriazole are particularly preferred.

The reactions are in general carried out in a temperature range from -20°C to +80°C, preferably from 0 C to In general, the reaction is carried out at normal pres- 10 sure. However, it is ealso possible to work at reduced S pressure or at elevated pressure from 0.5 to 5 bar).

The removal of the amino protective groups can likewise be carried out according to a customary method using acids, such as, for example, hydrochloric acid oi trifluoroacetic acid.

e* The removal of the amino protective groups is carried out in a manner known per se under acidic or basic conditions, or by reduction by means of catalytic hydrogenation, for example using Pd/C in organic solvents such as ethers, e.g. tetrahydrofuran or dirxane, or alcohols, e.g. methanol, ethanol or isopropanol.

The hydrogenation is in general carried out in a temperature range from 0 C to 80 0 C, preferably from 0 C to 40 0

C.

Le A 29 651 29 In general, the hydrogenation is carried out at an elevated pressure from 2 bar to 8 bar, preferably from 3 to 5 bar.

It is likewise possible, in particular in the case of acylamino protective groups, to remove these in one of the abovementioned ethers, using hydrides, such as, for example, lithium aluminium hydride or sodium borohydride, at room temperature and normal pressure.

The reduction of nitro compounds (R 1

R

2

R

3 and/or R 4 to 10 the corresponding amino compounds is carried out by 00 .customary methods, but preferably in the system ammonium chloride/Fe/H 2 0 in 2-methoxyethanol in a temperature range from +10 0 C to +150 0 C, preferably from +80 0 C to *oo* +130 0 C, and at normal pressure.

**g0 The alkylation of amino groups is carried out using either sulphonic acid esters or substituted or unsubsti- 000 tuted (Ci-C0)-dialkyl sulphonates or (C,-C,)-diaryl sulphonates, preferably methyl iodide or dimethyl sulphate, or using formaldehyde/sodium borohydride in one of the 20 abovementioned ethers, preferably tetrahydrofuran, in the presence of acids.

*0 0 The alkylation is in general carried out in one of the abovementioneu solvents, preferably in dimethylformamide in a temperature range from 0 0 C to +70 0 C, preferably from 0°C to +30 0 C, and at normal pressure.

Le A 29 651 30

_~I

The reductions of the carbonyl functions of the compounds of the general formulae (IV) and (VII) and intermediates having this group which occur in part are in general carried out using reducing agents, such as, for example, lithium aluminium hydride, using borane solution in tetrahydrofuran or using borane-dimethyl sulphide (complex in tetrahydrofuran) in a temperature range from 0 C to +70C, preferably from +20°C to +65°C, and at normal pressure and subsequently taking up in acids. Borane solution in tetralydrofuran is preferred.

Suitable acids for individual process steps are in general protic acids such as, for example, hydrochloric acid or sulphuric acid. Sulphuric acid is preferably employed.

o The acid is in general employed in an amount from 1 mol to 20 mol, preferably from 1 mol to 5 mol, in each case relative to 1 mol of the reactant.

The compounds of the general formula (II) are known in some cases or are new and can then be prepared, for 20 example, by reacting compounds of the general formula

(XI)

RI

R

2

OH

3 (XI) R3 R4 Le A 29 651 31 in which

R

1

,R

2 R 3 and R 4 have the abovementioned meaning, first with compounds of the general formula (XII)

R

x ,0 2 -T

(XID

in which

R

5 has the abovementioned meaning, X represents halogen, preferably bromine and T represents C-C 4 -alkyl, in one of the abovementioned solvents and a base, prefer- 10 ably acetone and potassum carbonate, and then saponifying the ester as described above.

The reaction is in general carried out in a temperature range from +20°C to +100°C, preferably from +20 0 C to and at normal pressure.

S*•

The compounds of the general formulae (XI) and (XII) are known per se.

The compounds of the general formula (III) are known per se.

Le A 29 651 32 I I~rM The compounds of the general formula (IV) are new and can be prepared, for example, as described above.

The compounds of the general formula are known in some cases or are new and can then be prepared, for example, by reacting compounds of the general formula (II) first with compounds of the general formula (XIII)

R

6

R

7 X-NN NH C(XII) in which e* R6,R 7 and X have the abovementioned meaning, as described above in process and then reducing the carbonyl function, likewise as described above.

The compounds of the general formula (XIII) are known.

The compounds of the general formula (VI) are known.

The compounds of the general formula (VII) are for the most part new and can be prepared as described above.

15 The compounds of the general formula (VIII) are known in some cases or are new and can then be prepared, for example, by reacting compounds of the general formula (XIII) with 4,4-bis-(substituted 4-phenyl)butanoic acids in one of the abovementioned substituted solvents, bases and auxiliaries, preferably in the system tetrahydrofuran/ Le A 29 651 33 dicyclohexylcarbodiimide/hydroxybenzotriazole in a temperature range from 0 C to +300C, preferably at room temperature and normal pressure, and then removing the benzyl group with ammonium formate/Pd/C in ethanol/water in a temperature range from +20°C to +10 0 C, preferably from +30°C to +50 0

C.

The compounds of the general formula are for the most part new and can be prepared, for example, by reacting compounds of the general formula (II) with compounds of the general formula (XII), likewise in the system hydroxybenzotriazole/dicyclohexylcarbodiimide/tetrahydrofuran at room temperature and normal pressure.

The inhibitors described here are inhibitors of HIV protease and as such can be employed for all purposes for which enzyme inhibitors are suitable. This is, for example, use in diagnosis, in order to improve the precision and selectivity of enzyme activity measuretoo* ments. In affinity chromatography, they can be used as an affinity label and in research they can be used to 20 elucidate reaction mechanisms and the specificity of enzymatic reactions.

0** Moreover, it has surprisingly been found that the compounds of the general formula have an extremely potent action against retroviruses. This is confirmed by an HIV-specific protease enzyme test.

The results of the examples mentioned below were Le A 29 651 34 I determined by the HIV test system described in the following literature references [cf. Hansen, J., Billich, Schulze, Sukrow, S. and Mlling, K.

(1988), EMBO Journal, Vol. 7, No. 6, pp. 1785 1791]: purified HIV protease was incubated with synthetic peptide which imitates a cleavage site in the Gag precursor protein and is an in vivo cleavage site of HIV protease. The resulting cleavage products of the synthetic peptide were analysed by means of reverse phase high performance liquid chromatography (RP-HPLC) The ICs values indicated relate to the substance concentration which causes a 50% inhibition of protease activity under .0 the abovementioned test conditions.

Table 1: Ex. No. Inhibition at ICs 0

(PM)

240 Vg/ml 3 76 77 4.8 20 13 91 0.48 14 99 1.1 15 92 0.4 16 59 17 86 25 22 81 26 97 27 78 81 32 67 30 33 56 34 99 0.17 37 61 39 77 84 41 95 2.1 44 99 26 Le A 29 651 35 The cor',ounds according to the invention are useful active compounds in human and veterinary medicine for the treatment and prophylaxis of disorders caused by retroviruses.

Indication areas in human medicine which can be mentioned, for example, are: The treatment and prophylaxis of human retrovirus infections.

For the treatment or prophylaxis of disorders (AIDS) 10 caused by HIV I (human immunodeficiency virus; formerly called HTLV iiI/LAV) and HIV II and the stages associated therewith such as ARC (AIDS- ,related complex) and LAS (lymphadenopathy syndrome) see* and also the immunodeficiency and encephalopathy *0 caused by this virus.

For the treatment or the prophylaxis of an HTLV-I or HTLV-II infection.

*gee For the treatment or the prophylaxis of the AIDS carrier state (AIDS transmitter state).

20 Indications in veterinary medicine which can be listed, Soo* for example, are: Infections with a) maedi-visna (in sheep and goats) b) progressive pneumonia virus (PPV) (in sheep and goats) c) caprine arthritis encephalitis virus (in sheep and t~A -A329 651 36 l .9 o.

*r 9 o 9 9 .9 s goats) d) zwoegersiekte virus (in sheep) e) infectious anaemia virus (of the horse) f) infections caused by feline leukaemia virus g) infections caused by feline immunodeficiency virus

(FIV)

h) infections caused by simian immunodeficiency virus (SIV) The abovementioned items 2, 3 a.d 4 are preferred from the indication area in human medicine.

he present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formula (1j or which consist of one or more active compounds of the formula and processes for the production of these preparations.

T

he active compounds of the for ula should be present in the abovementioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture.

Apart from the compounds of the formula the abovementioned pharmaceutical preparations cun also contain other pharmaceutical active compounds.

The abovementioned pharmaceutical preparations are prepared in a customary manner according to known Ze A_29_651 37 .9 9 i ;1 methods, e.g. by mixing the active compound or compounds with the excipient or excipients.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts from about 0.5 to about 500, preferably 1 to 100, mg/kg of body weight per 24 hour's, if appropriate in the form of several individual doses, to achLeve the desired results. An individual dose contains the Pctive compound or compounds preferably in amounts about 1 to about 80, in particular 1 to 30, mg/kg of body weight.

However, it may be necessary to depart from the doses mertioned, mainly depending on the species and the body weight of the subject to be treated, the nature and the severity of the disease, the type of preparation and the administration of the medicament and also the period or interval within which administration takes place.

Starting Cmpound Example I 2,6-Difluozophenoxyacetic acid 38/0

'COH

4 g (30.8 mmol) of 2,6-difluorophenol, 4.3 g (30.8 mmol) Le A 29 61 38 of potassium carbonate and 4.7 ml (42.3 mmol) of ethyl bromoa.uetate are heated under reflux in 50 ml of acetone for 18 h. The solid is then filtered off with suction, and the filtrate is diluted with 200 ml of ether and washed three times with dilute hydrochloric acid. The organic phase is then dried (MgSO4) and concentrated in vacuo. 6.46 g of a crude product are obtained, which is dissolved in 800 ml of ethanol and treated with 120 ml of 1 N sodium hydroxide solution. The mixture is stirred at RT for 1 h, then concentrated in vacuo to 100 ml, acidified with 6 N HCl to pH 1 and extracted 5 timi a with dichloromethane. The organic phases are dried (MgS04) and concentrated. For purification, the residue is taken up in satd. NaHCO 3 solution c.nd washed twice with ether. The 15 aqueous phase is then acidified again and further pro- S. cessed as described above. After concentration, 4.4 g of the carboxylic acid are obtained.

4-bis-(4-Fluorophenyl)butyl]-4-[(2, 6difluorophen- 20 oxy)acetyl]piperazine 0 NN (CH) CH F 0

F

g (13.3 mmol) of the acid from Example I, 1.81 g LeA 29 651 39 (13.3 inmol) of hydroxybenzotriazole, 3.03 g (14.7 mmcl) of dicyclohexylcarbodiimide and 4.4 g (13.3 mmol) of 4-bis-(4-fluorophenyl) -butyl]piperazine are stirred at RT for 36 h in 100 ml of tetrahydrofuran. The solid is then filtered off with suction, the filtrate is concentrated, the residue is taken up in ethyl acetate and the al.ution is washed 3 times with water. The organic phase is *then drieot (MgSO 4 and concentrated, and the residue is chromatogv'aphed on silica gel using dichloromethane/ methanol (50:1).

Yield: 4.58 g (68.5%) Rf(CH 2 C1 2

/CH

3 OH 50:1) 0.27 *.Exaxmle- III *see Diethyl 2, 4-difluorophenoxymnalonate

F

00 2

H

**550S 63.6 g (0.49 mol) of 2,4-difluorophenol are added with ice-cooling to a solution of 38.1 g (0.54 mol) of sodium ethoxide in 750 ml of ethanol. After 11 at RT, 99.6 g (0.51 mel) of diethyl chloromalonate in 250 ml of ethanol are added and the mixture is stirred at RT for 18 ho It is then adjusted to pH 7 using 1 N HUl and filtered, and the filtrate is concentrated. The residue is chromatographed on silica gel using dichloromethane.

Yield: 47 g (34%) Le A 29-651 40 Example I Monoethyl 4-difluorophenoxymalonate C0 2

C

2

H

C0 2

H

39.5 g (0.14 mol) of the diester from Example III in 700 ml of THF are treated at 0 0 C with 150 ml of 1 N NaOil.

After 3 h at 0 0 C, the mixture is adjusted to pH 2 using 1 N HCi and concentrated down to about 100 ml. It is 0e extracted 3 times with ethyl acetate, and the extract is dried (MgSO 4 and concentrated. The residue is chromato- ~.graphed on silica gel using dichioromethane/ethanol Yield: 17.1 g (48%) ExampleV to (S)-l-(4,4-bis-(4-Fluorophenyl)butanoyl)-2-methy.piperazine

F

HN~'N~~(CH

2 2 7CN ~CH3 -l-Benzyl-3-methylpiperazine and 4, 4-bis- (4-f luorophenyl) butanoic acid are reacted to give the aimide as Le A 29 651 41 described in Example II. 556 mg (1.24 mmol) of this compound are stirred in 2.9 ml of ethanol and 0.6 ml of water with 195 mg (3.1 mmol) of ammonium formate and 195 mg of palladium on active carbon at 50*C for 30 min. The mixture is then filtered, the filtrate is concentrated and the residue is chromatographed on silica gel using dichloromethane/methanol as the eluent.

Yield: 389 mg (88%) Rf (dichloromethane/methanol 9:1) 0.27 Preparation Examples 0 Example 1 *see ae l-[4,4-bis-(4-Fluorophenyl)butyl]-4-[2-(2,6-difluorophenoxy)ethyl]piperazine

F

S

F

N N- (CH2) CH

F

4.06 g (8.1 mmol) of the amide from Example II are 15 treated in 100 ml of abs. tetrahydrofuran (THF) with 32.6 ml (32.6 mmol) of a 1 M borane solution in THF. The mixture is allowed to stand at RT overnight, 'then it is introduced into 100 ml of 5 N HC1 and heated at 60°C for min. After cooling, it is adjusted to pH 11 with cone.

sodium hydroxide solution and extracted 3 times with Le A 29 651 42 I I ethyl acetate. The combined organic phases are dried (MgS04) and concentrated and the residue is chromatographed on silica gel using ethyl acetate/acetone (20:1) as the eluent.

Yield: 3.7 g, oil Rf (acetic acid/acetone 10:1) 0.52 The oily product is dissolved in 50 ml of ether and treated with 10 ml of satd. ethereal hydrochloric acid.

The solid obtained (the dihydrochloride of the title compound) is filtered off with suction, washed with ether and dried.

Yield: 3.5 g Example 2 :1 -[4,4-bis-(4-Fluorophenyl)butyl-4-[2-(2-aminophenoxy)ethyl]piperazine

F

00

NH

2 N N 1 N (CH CHF g s

F

2-Nitrophenol is converted, as described for Example 1, into l-[4,4-bis-(4-fluorophenyl)-butyl]-4-[2-(2-nitrophenoxy)ethyl]piperazine. 1 g (2.02 mmol) of this substance (free base) in 8 ml of 2-methoxyethanol is heated to reflux with 646 mg (12.1 mmol) of ammonium chloride and 2 ml of water and treated in portions with 646 mg of Le A 29 651 43 iron filings (about 15 min). The mixture is heated under reflux for 3 h and cooled, the solid is filtered off with suction through kieselguhr and washed with hot methanol, and the filtrate is concentrated in vacuo. The residue is chromatographed using dichloromethane/methanol (20:1) as the eluent.

Yield: 828 mg (88%) Rf (dichloromethane/methanol 20:1) 0.27 A portion is converted into the trihydrochloride as described in Example 1.

.9 Example 3 1-[4,4-bis-(4-Fluorophenyl)butyl]-4-[2-(2-N,N-dimethylaminophenoxy)ethyl]pipe.azine

F

/N(CH

32 N NNN- (CH 2 3

C

*99 121 mg (0.26 mmol) of the aniline from Example 2 are 15 treated in 1.8 ml of tetrahydrofuran with 69 mg (1.82 mmol) of sodium borohydride and cooled to 0°C. A solution of 195 il of 3 M sulphuric acid and 110 pl (1.56 mmol) of 35% formaldehyde in water is then added, and the mixture is rendered alkaline using 2 N sodium hydroxide solution and extracted 3 times with ethyl acetate. The combined organic phases are dried (MgSO 4 Le A 29 651 44 and concentrated, and the residue is then chromatographed on silica gel using dichioromethane/methanol (50:1).

Yield: 53 mng (41%) ExaMple 4 1-[4,4-bis-(4-Fluorophenyl)butyl-4-[2-(2-acetylaminophenoxy) ethyl] piperazine 0 HN>

CH

3 N N (C H 2 3 C 10mn:hemxueistetd hs. C Na.Q F outo and extracted 3 times with dichloromethane. The combined organic phases are dried (MgSO 4 and concentrated and the '~.residue is chromatographed on silica gel using dichloromethane/methanol (50:1).

.99: 15 Yield: 401 mg (88.5%) Rf (dichloromethane/methanol 20:1) 0.56 ExaMple 1- [4,4-bis- (4-Fluorophenyl) butyl 3-4- (N-methyl-acetylaminophenoxy )ethyl] piperazine L~e A-29 651- 5- 45 O

F

N-CH

3 N-NC

(CH

2 3

F

389 mg (0.77 mmol) of the acetanilide from Example 4 in 5.8 ml of dimethylformamide are treated at -20°C with mg (1.0 mmol) of 80% NaH suspension and 275 mg (1.0 mmol) of methyl iodide. After 10 min, the mixture is 5 diluted with water and extracted 3 times with ether, and the combined organic phases are dried (MgSO 4 and concentrated. The residue is chromatographed on silica gel using dichloromethane/methanol (20:1).

Yield: 124 mg (31%) 10 Examle 6 1-[4,4-bis-(4-Fluorophenyl)butyl]-4-[2-(2-N,N-ethylmethylaminophenoxy)ethyl]piperazine

N-CH

F

103 mg (0.2 mmol) of the compound from Example 5 in ml of ether are stirred at RT for 1 h with 15 mg Le A 29 651 46 (0.4 mmol) of lithium aluminium hydride. Water is then added, the mixture is rendered acidic with sulphuric acid and washed with ethyl acetate, and the aqueous phase is rendered basic with 2 N sodium hydroxide solution and extracted 3 times with ethyl acetate. The combined organic phases are dried (MgSO4) and concentrated, and the residue is chromatographed using dichloromethane/ methanol (20:1) as the eluent.

Yield: 63 mg (63%) 10 Example 7 l-[4,4-bis-(4-Fluorophenyl)butyl]-4-[2-(4-chloro-2hydroxycarbonylphenoxy)ethyl]piperazine F F

N

(CH 3-CH

CO

2

H

As described in Example 1, 1-(4,4-bis-(4-fluorophenyl)butyl]-4-[2-(4-chloro-2-methoxycarbonylphenoxy)ethyl]- 15 piperazine is prepared starting from methyl 5-chloro-2hydroxybenzoate. 8.3 g (15.3 mmol) of this compound are stirred at RT for 18 h in 100 ml of methanol and 15 ml of water in the presence of 1.1 g (20 mmol) of potassium hydroxide. The mixture is then concentrated, the residue is partitioned between ethyl acetate and water, and the mixture is adjusted to pH 2 using 6 N hydrochloric acid.

Le A 29 651 47 The organic phase is separated offr dried (MgSO 4 and conc.antrated to 50 ml. After treating with ether, a solid is obtained, which is filtered of f with suction arid dried.

Yield: 6.5 g Rf (dichloromethane/ethanol =0.13 Example 8 1-[4,4-bis-(4-Fluorophenyl)butylJ-4-[(2-[4-chloro-2-(N- 0 -1-tert-butoxycarbonyl-2-methylpropyl) axinocarbonyl) phenoxy]ethyljpiperazine 0 'F c, N N N (CH03- CHO 0N C0 2

-C(CH

33 529 mg (1 mimol) of the acid from Example 7 and 174 mg (1 mmcl) of L-valine tert-butyl ester are coupled accord- :::o:ing to the method from Example II. Purification is carried out by chromatography on silica gel using dichloromethane/ethanol as the eluent.

Yield: 630 mg (92%1 Rf (dichloromethane/ethanol 20:1) 0.45 Le A 29 651 48 ExaMple 9 1-[4,4-bis-(4-Fluorophenyl)butyl]-4-[2-[4-chloro-2-(N- -l-hydroxycarbonyl-2-methylpropyl) aminocarbonyl) phenoxy Jethyl] piperazine

F

C.

C02 36 mg(Oo5 mml) o th estr fom Eampe 8 re dde at nIm fdclrmthn o1m ftiloo solu5t360 n (0.5 treate) of th eter/omexamle ethar adde actca.Temixture is allowed to setltesletansdecate ofor and the residue is dried.

Yield: 310 mg (94%) 1-(4,4-bis-(4-Fluorophenyl)butyl]-4-( fluorophenoxy) propyl ]piperazine LeA_ 29__M 4 49 0

F

The title compound is prepared by coupling 2,4-difluorophenol with ethyl (R/S)-2-bromopropionate according to the method of Example I and further conversion of the ester obtained analogously to Example 1.

,5 Rf (acetic acid/acetone 10:1) 0.56 **a 1-[4,4-bis-(4-Fluorophenyl)butyl)-4-[(2R/S)-2-(2,4difluorophenoxy) -2-ethoxycarbonylethyl ]piperazine

F

C0 2

C

2

H

5 coc. C.

F 0CH

F

The carboxylic acid from Example IV is reacted to give the amide as described for Example II. 32.2 g (61 mmol) of the amide in 200 ml of tetrahydrofuran (THF) are treated with ice-cooling with 135 ml of a 2 M solution of borane/dimethyl sulphide in THF and the mixture is kept at RT for 8 h. It is then treated with ice-cooling with Le A 29 65!1 50 ml of 15% strength hydrochloric acid, heated to for 20 min and adjusted to pH 10 using sodium hydroxide solution. The mixture is extracted twice using ethyl acetate, dried (MgSO 4 and concentrated. The residue is chromatographed on silica gel using dichioromethane! ethanol (20:1) as the eluent.

Yield: 19.5 g R, (dichloromethane/ethanol 15:1) 0.6 Exainnie 12 1-[4,4-bis-(4-Fluorophenyl)butyl3-4-[(2R/S)-2-(2,4difluorophenoxy)-2-(N-(is)-1-tert-butoxycarbonyl-2methylpropyl)aminocarbonyl)ethyl]piperazine

F

0,HNXY C0 2

-C(CH

3 F a N N- (CH 3

CH

F

F

The ester from Example 11 is saponified and the acid is reacted with (L)-valink, tert-butyl eater to give the amide as described in Examples 7 and 8.

4:004: RI (dichloromethane/othanol 15*01) 0.52 (1st diastereomer) 0.38 (2nd diastereomer) rin A 29_651 51 Example 13 [4,4-bis- (4-Fluoropheny) butylI -2--iethyl-4- (2,f 4difluorophenoxy)ethyl)p iperazine

F

F "N N- (CH 2 3

-CH

F C- H 3

F

*0I P TIhe piperazine from Example V is coupied with 2,4-di- 5 fluorophenoxyacetic acid (prepared from ~,4-difluorophenol and tert-butyl bromoacetate analogously to 0 0 Example I) to give the anhydride analogously to Example XI then both amide groups of the intermediate are reduced aaalogously to Example 1 using 10 eq of 10 borane in tetrahydrofuran.

OP..

Yield: 85% (over two steps) MS (FAB): /z =501 Rf (d:lchloromethaneiethanol 9:1) 0.51 I 0 Exampef 14 15 ()-4*([4,4-bis-(4-Fluorophenyl)butyl]-2-methyl-l-[2-(2,4difluorophenox? ethylj]piperazine Le A 29 651-5 52

';L.I*IPIIIII

H

3

C

F N Q >N N -(CH 2 3

CH.-.

CHF:

2,4-Dif:Luorophenoxyacetic acid (prepared from 2,4-difluorophienyl and tert-butyl bromoacetate analogously to Example I) and (S)-1-benzyl-3-methylpiperazine (see Example V) are reacted to give the amnide analogously to Example II. The benzyl group is then removed as shown in 0Example V, the amide with 4,4-bis- (4-f luorophenyl) butanoik acid is formed (see Example V),I and finally both amide groups are reduced as shown in Example 13.

MS (FAB): m/e 501 Rf (dichloromethane/methanol 9:1) 0.61 The compounds shown in Tables 1, 2 and 3 are prepared in analogy to the procedure of Example 4: Le A 29 _651 53 Table 1:*

A

R2 0- (CH 2 (CH- CH

R

3

R

4

F

Ex. No. R' R

R

3

R

H F H -F 0,53/1 :.16 H H -CH 3

-CH

3 0,59/1 H cI H CH 3 0,57/1 Dos18 H H H -NO2 0,29/11l 19 H H H -oH 0118/I11 H H Cl 7Cl 0.32/1ll 21 H -CHO H -OCH 3 0.4/ IV 22 H -CH 3 H -OCH 3 0,57/1 23 -C 6

H

5

-NO

2 H H 0,16/Ill :24 H H H, -C 6

H

5 0,19/11l -6425 H H H -F Le A 29_651 54 Table 2: R2 Ex. No. RI~ 26 H

(CH

2 2 N I Rf 0.62/1 *0.

Table 3:

R

2 Ex. No.

27 28

(CH)-

H

0.53/IT 0.57/11 4* 0 The compounds shown in Table 4 are the procedures of Examples 2 6: prepared in analogy to Le A 29 651 55 Table 4: Rl 2 0 0- (C H 2 2 NN N- (CH)-

R

3 R 4 0S 0 0*0 0 *0*0 Ex. Vo.

29 30 31 32 33

H

H

-CH

3

H

H2

H

.CI

H

-COCH

3

*CH

2 0H

-NH

2

-N(CH

3 2

H

-NH

2

H

H

H4

H

NH

2

H

*N*CH

3

CO-CH

3

*N-CH

3 0 2

H

Rf 0,49/V 0,83/V 0,32/V 0,53/V 0.30 /VI 0,30/VI 0 **00 The compounds shown in Table 5 are prepared in analogy to the procedures of Examples 7 9: Le A 29 651 56 Table

(CH

2 2 N N (CH 2 3 Ex. No. R R 2

-CONH

2 0,27 /V -CON HCH 2 Ph 0,36/1V 0* The compounds shown in Table 6 are prepared in analogy to the proc-:edure of Example Table 6:

F

R

2 CH- cH 2 N N- (CH- CH

R

3

R

4 4* Le A_29 651 7 57 Ex. No. x No 2 R 3

H

H

-CI

-CF

3

H

C H 3

-CF

3

H

H

-OH

3

H

CH

3

H

-OH

3

-OH

3

-OH

3

-OH

3

-OH

3 0,59/1 0,59/1 0,63 /1 0,60/1 0,66/1 in analogy to

-(OH

2 4 The compounds shown in Table 7 are prepared the procedures of Examples 11 and 12: Table 7: R,

R

R2 O-H;'-UlCH 2 N (CH 2 )r-C

R

3

R

4 Ex.* No. R' R 2 R 3 R4 R6 -F -CONHCH 2 Ph 0,20/11l H -F H The the compounds procedure shown in Table of Example 13: 8 are prepared in analogy to Le A 29 651 -5 58 Table 8:

R

1

RSR

R2 0- CH 2 -N N

R

3 R 4 Ex. No. R 1 R 2 R 3 R4 R 5 R t H -F H .F H (R)-CH 2 OH 0,47/ 11 S S S S

*SS*

S.

S

S

The compounds shown in Table 9 are prepared in analogy to the procedure of! Example 14: Table 9:

R

1

R

5

R

R

2 u- CH2-1-N N- (CH)-C 8 3

R

4 OS S 5.55.5 Le A 29 651 -5 59 Ex.

No. R 2 RR4 R1 R 5

R

6 Rf 0,57/11i 44 H H 00H 3 -F H -F 46 -F H -F

-(OH

2 2

(S)-CH

3 H H (R)-CHZOH 0,45/11 H H (S)-0H 2

-C

6 HS 0,7211 0* S a Ca S S *5 5 0 S*S S

S

Rf values in solvent miixtures: I ethyl acetate/acetone 10:1 II dichloromethane/methanol 9:1 III =dichioromethane/methanol 50:1 IV -ethyl acetate/acetone 1:1 V dichioromethane/methanol 20:1 VI =acetone Le A 29 651 60

Claims (2)

1. A method for the treatment of retroviral infections wherein there is administered, to a subject in need of such treatment, a substituted piperazine of the general formula R R 5 F 6 R 7 Re R 2 OJ" 0 CH-- N N (CH 2 3 CH R 3 R 4 'Rq in which RI R and R 4 are identical or different and represent hydrogen, nitro, halogen, carbixyl, hydroxyl, formyl, straight-chain or branched alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, trifluoromethyl, phenyl or represent straight-chain or branched alkyl having S* up to 8 carbon atoms, which is optionally sub- stituted by hydroxyl or protected hydroxyl, or represent a group of the formula -NRI 1 R" or -CO-A, *S in which R"1 and R 1 identical or different and denote hydrogen, phenyl, benzyl, an amino protective group or straight-chain or branched alkyl having up to 8 carbon atoms, R' I and R 11 together with the nitrogen atom, fo.rm a 5- to 7-membered, saturated heterocycle, A denotes the abovementioned group -NR 1 R' 1 or the radical of the formula R13 -NR 12 (CH 2 )a-COR 1 in which R1 0 and R n hav° the abovementioned meaning, R 12 denotes hydrogen or straight-chain or 0. branched alkyl having up to 4 carbon atoms, *see R" denotes cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms or hydrogen, or e. ~denotes straight-chain or branched alkyl having up to 8 carbon atoms, where the alkyl is optionally substituted by methylthio, hydroxyl, mercapto, guanidyl or by a group of the formula -NR 15 R or 9 in which R 1 and R 1 independently of one another Le A 29 651 62 denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, and R" denotes hydroxyl, benzyloxy, alkoxy having up to 6 carbon atoms or the abovementioned group -NRR 1 6 in which R and R" have the abovementioned meaning, or the alkyl is optionally substituted by cyclo- alkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which for its part is substituted by hydroxyl, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group -NR"R 16 in which R 1 and R" have the abovementioned meaning, S or the alkyl is optionally substituted by a 5- to

6-membered nitrogen-containing heterocycle or indolyl, 63 in which the corresponding -NH functions are optionally protected by alkyl having up to 6 carbon atoms or by an amino protective group, and a denotes the number 0 or 1, R 14 denotes hydroxyl or straight-chain or branched alkoxy having up to 8 carbon atoms, or or R 2 and R 3 or R 3 and R 4 together, including the phenyl double bond,a partially unsaturated 5- to 7-membered carbocycle, R 5 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or represents a group of the formula -C02R 1 8 in which R" denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or a hydroxyl protective group, or 64 W r epr esentts ai group of tho formiula M-, in which A has the abovementioned meaning of A and is identical to or different from this, or R' and RI, including the oxygen atom and the phenvl ring, together form a 5- to 6-membered, unsatu- rated hbetercycle, U' and R' are identical or difforent and represent j hydrogen, carboxyl or straight-chain or branched alkyl having up to 8 carbon atoms, which li optionally substituted by hydroxyl or phenyl, or creprocent straight-chain or branched alkoxy- carbonyl having up to 8 carbon atoms, HI and R' are identical or different and represent halogen, cyano, nitro, azido or hydroxyl, S. and their salts. 2ao o S2. A method according to Claim 1 S in which R 1 p 2 R 3 and A4 are identical or dif ferent and, represent hydrogen, nitro, fluorine, chlorine, bromine, carboxyl, hydroxyl, formyl, straight- chain or branched alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms, trifluoro- methyl, phenyl or represent straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally sub- stituted by hydroxyl or protected hydroxyl, or 2, 'apresfent a group of the formula -NR' 0 R' 1 or -CO-A, in which 0*RI' and R" are identical or dtfff-ent and denote hydrogen, phenyl., benzyloxycarbonyl, butyl, tert-butoxycarbonyl (BOC), acetyl, benzyi. or straight-chain or branched alkyl having up to 6 carbon atoms, or RIO 0 and R 11 together with the nitr~gen~ atom, form a pyrrolidine or piperidins ring, A denotes the abovementioned group -NR 0 fl" or S the radical of the formula -NR 12 (CH 2 )a-COR 14 in which LeA 29 651 66 R" and R" have the abovementioned meaning, R' 2 denotes hydrogen, methyl or ethyl, R 13 denotes cyclopentyl, cyclohexyl, phenyl or hydrogen, or denotes straight-chain or branched alkyl having up to 6 carbon atoms, where the alkyl can optionally be substituted by methylthio, hydroxyl, mercapto, guanidyl, amino, carboxyl or H 2 N-CO-, or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which for its part can be substituted by fluorine, hydroxyl, nitro or alkoxy having up to 4 carbon atoms, s.oa or the alkyl is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, where the corresponding -NH ~functions are optionally protected by alkyl having up to 4 carbon atoms or by an amino protective group, R" denotes hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms, LegA 29 651 67 a denotes the number 0 or 1, S S S o S. SS S .5.5 55 S S 5* 5 or R 2 and R 3 or R' and R 4 in each case together, including the phenyl double bond, form a cyclohexenyl ring, R 5 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or represents a group of the formula -CO 2 R' 8 in which R 1 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, acetyl or benzyl, or R 5 represents a group of the foi,mula -CO-B, in which B has the abovementioned meaning of A and is identical to or different from this, or R' and R 5 including the oxygen atom and the phenyl ring, together form a chroman ring, 5.95 SQ.. 0 S9 se e SS@S 00 Le A 29 651 68 R' and R' are identical or different and represent hydr ogen carboxyl oi strai qht-chain ror branchied alkyl having up to 6 carbon atoms, which i optionally substituted by hiy droxyl or phenyl, or represent straight-chain or branched alkoxy- carbonyl having up to 6 carbon atoms, R' and R' are identical or different and represent fluorine, chlorine, cyano, nitro, azido or hydroxyl, and their salts. 3. A method according to Claim 1 in whc RI t44 'adR r dntclo ifrn n rersn 44doenirfurne hoie up to in whichtm, hc ptoalysb arepresent a roupn i tefrmu luorie, orine,-A :04 i broinec abxh hdoyfrml tagt Le A 2 9 6.5 1 69 R 10 and R 1 are identical or different and denote hydrogen, phenyl, benzyl, benzyioxycarbonyl, butyl, tert-butoxycarbonyl (BOC), acetyl or straight-chain or branched alkyl having up to 4 carbon atoms, or R 10 and R 11 together with the nitrogen atom, form a pyrrolidine or piperidine ring, denotes the abovementioned group -NR'OR!3' or the radical of the formula INR 12 'J'(0H 2 )a-C0R 14 in which R' 0 and have the abovementioned meaning, RXz denotes hydrogen, methyl or ethyl, R' 3 denotes cyclopentyl, cyclohexyl, phenyl. or hydrogen, or denotes straight-chain or branched al~kyl. having up to 4 carbon atoms, where the alkyl can be optionally substituted by methylthio, hydroxy., mercapto, guariiLdyl, amino, carboxyl Or H 2 N-CO-t Le -A-29-651 7o- 70. or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which for its part can be substituted by fluorine, hydroxyl, nitro or alkoxy having up to 4 carbon atoms, or the alkyl is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, where the corresponding -NH functions are optionally protected by alkyl having up to 4 carbon atoms or by an amino protective group, R" denotes hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, a denotes the number 0 or 1, or R 2 and R 3 or R 3 and R 4 in each case together, including the phenyl double bond, form a cyclohexenyl ring, e R 5 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or Srepresents a group of the formula -CO 2 R O *Voo: in which R" denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, acetyl or Le A 29 651 71 1henvy I or R' represents a group of the formula -CO-B, in which B has the abovementioned meaning of A and is identical to or different from this, 0, 0@ a 00 0*000 S..4 0 0 V too to0 R' and RI, including the oxygen atom and the phenyl ring, together form a chroman ring, RI~ and RI are identical or different and represent hydrogen, carboxyl or straight-chain or branched al'kyl having up to 4 carbon atoms, which is optionally st" jtituted by hydroxyl or phenyl, or represent s ght-chain or branched alkoxy- carbonyl havL.sy up to 4 carbon atoms, RI and RI are identical or different and represent fluorine, chlorine, cyano, nitro or hydroxy., and their salts. eT q 72 P:kWPflOCNSSPtC\4310JGS. 12/3/91 4. A method according to claim 1 where there is administered a pharmaceutical composition containing one or more of the compounds of the general formula as defined in claim 1, in association with one or more pharmaceutically acceptable carriers. DATED this 12th day of March, 1997. BAYER AKTLENGESELLSCHAFT By Its Patent Attorneys 66: DAVIES COLLISON CAVE 6S S 6* S S S S SGS SS S S SO S 055 5 5555 I S S S. S S S S .555 S 0*@S *S 6@ 5 9 SOS. S S 5606 55 55 *5 Substituted penrazines A bs tr a ct The present invention relates to substituted piperazines of thto general formula (I) R, R5 R 6 R 7 R 0 Cr N \jN (OH 2 3 C 8 in which the substituents ha;e the meaning indicated in *the description, processes for their preparation and their use as antiretroviral agents. Le A 29651 Foreigrn countries