Lipid alcohols as new immunosuppressive and antiviral drugs

Details Lipid alcohols as new immunosuppressive and antiviral drugs Lipid alcohols as new immunosuppressive and antiviral drugs

1998-06-22

2001-01-23

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S506000, C514S712000, C514S715000, C514S722000, C514S723000

Reexamination Certificate

active

06177469

ABSTRACT:

This Application is a 371 of PCT/EP96/04438 filed Nov. 15, 1996 which claims Priority From German Patent Applicant 195 38 402,4 filed Oct. 14, 1995
The present invention concerns lipid alcohols as new immunosuppressive and antiviral pharmaceutical agents. Lipid alcohols are known as intermediate products for the production of e.g. phosphocholines or liponucleotides. Such intermediate products are described for example in the following patent applications and literature references: [J. Med. Chem. 34, 1377 (1991), Tetrahedron Lett. 26, 1167 (1985), Gazz. Chim. Ital. 116, 25 (1986), Lipids 22, 947 (1987), EP 90 11 6298, DE 36 38 126, EP 0 050 327]. Lipids with chains interrupted by heteroatoms in phosphocholines are described in DE 39 29 217.7 and WO 91/05558 and the documents EP 0 350 287, WO 90/00555, PCT/EP 93/00294, PCT/EP 93/00295, EP 0545966 and PCT/EP 93/02101 show the use of corresponding lipid moieties as specific carriers in covalent conjugates with nucleoside monophosphates.
In none of the cases is a pharmacological effect of the lipid alcohols used as an intermediate product in the production described.
Even in a routine examination of these compounds for an antiviral action in the known test systems for HIV (e.g. MT2/MTT test or corresponding tests with M/M etc.) no direct antiretroviral effect could be found (up to 100 &mgr;g/ml).
The present invention concerns new immunosuppressive and antiviral pharmaceutical agents using lipid alcohols of the general formulae I and II
in which
R
1
represents a straight-chained or branched, saturated or unsaturated alkyl chain with 1-30 carbon atoms which can optionally be substituted once or several times by halogen, C
1
-C
6
alkoxy, C
1
-C
6
alkylmercapto, C
1
-C
6
alkoxycarbonyl, carboxy, C
1
-C
6
alkylsulf inyl or C
1
-C
6
alkylsulf onyl groups,
R
2
represents hydrogen, a straight-chained or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms which can optionally be substituted once or several times by halogen, C
1
-C
6
alkoxy, C
1
-C
6
alkylmercapto, C
1
-C
6
alkoxycarbonyl or C
1
-C
6
alkylsulfonyl groups,
X represents a valency dash, oxicarbonyls carbonyloxy, amidocarbonyl, carbonylamido, oxygen, sulphur, a suif inyl or sulfonyl group
Y represents a valency dash, oxicarbonyl, carbonyloxy, amidocarbonyl, carbonylamido, oxygen, sulphur, a sulfinyl or sulfonyl group
n represents an integer from 1 to 5 inclusive, as well as tautomers thereof and combinations containing these compounds with other active substances.
Since the compounds of the general formulae I and II contain asymmetric carbon atoms, all optically active forms and racemic mixtures of these compounds are also a subject matter of the present invention. As far as possible the invention also includes pharmacologically acceptable (acid addition) salts.
R
1
in the general formulae I and II is preferably a straight-chained or branched, saturated alkyl chain with 7-18 carbon atoms which can optionally be substituted once or several times by halogen, C
1
-C
6
alkoxy, C
1
-C
6
alkylmercapto or C
1
-C
6
alkylsulfonyl groups. Unbranched saturated alkyl residues with 8-15 carbon atoms are particularly preferred for R
1
. R
1
in particular represents a nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl residue.
Methoxy, ethoxy, butoxy and hexyloxy groups come preferably into consideration as C
1
-C
6
alkoxy substituents of R
1
. If R
1
is substituted by a C
1
-C
6
alkylmercapto residue this is in particular understood as a methylmercapto, ethylmercapto, propylmercapto, butylmercapto and hexylmercapto residue.
R
2
preferably denotes a straight-chained or branched, saturated alkyl chain with 6-16 carbon atoms which in addition can be substituted by a C
1
-C
6
alkoxy or C
1
-C
6
alkylmercapto group or halogen.
R
2
is preferably a straight-chained C
8
-C
15
alkyl group which can in addition be substituted by a C
1
-C
6
alkoxy group or a C
1
-C
6
alkylmercapto group. R
2
in particular represents an octyl, nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl group. A methoxy, ethoxy, propoxy, butoxy and hexyloxy group preferably come into consideration as C
1
-C
6
alkoxy substituents of R
2
. If R
2
is substituted by a C
1
-C
6
alkylmercapto residue this is especially understood as a methylmercapto, ethylmercapto, butylmercapto and hexylmercapto residue.
Compounds of the general formula I are also preferred in which R
2
represents a hydrogen atom and Y equals oxygen or a valency dash.
In this case compounds are particularly preferred in which Y is a valency dash, R
2
represents hydrogen, X has the meaning stated above and R
1
represents an alkyl residue with 12-25 carbon atoms.
An unbranched, saturated C
12
-C
25
alkyl residue which is bound to the parent substance via X equals sulphur is especially preferred for R
1
in these combinations.
X is preferably sulphur, sulfinyl or sulfonyl and Y equals oxygen.
n preferably equals 1 to 3, it, however, particularly preferably equals 1.
The heteroatoms X and Y in the lipid part can only be replaced in special cases by the carboxylic acid esters known from lecithin since otherwise a hydrolytic cleavage to form the corresponding lysolecithin derivatives or glycerol esters would already occur in the serum or in the liver (first pass effect) with a corresponding more rapid elimination of the pharmacologically active substance. The thioether and ether lipids (X, Y=O,S) of this application do not exhibit this cleavage in the serum of various species including humans.
The therapy of malignomas and malignant neoplasias (carcinomas, sarcomas, haematological neoplasias), of inflammatory diseases or organ-specific and generalized autoimmune diseases as well as of diseases caused by (retro)viruses such as AIDS, ARC (AIDS related complex), cytomegaly, herpes or hepatitis is often associated with extreme side-effects in addition to the inadequate efficacy of the therapeutically active substances used. This effect is due to the low in vivo selectivity and the limited therapeutic range of the pharmacologically active substances that are used. The favourable pharmacological in vitro properties of the respective compounds are often not transferable to the in vivo conditions. Therefore for years attempts have been made to provide new substances by modifying the chemical structure of pharmacologically active substances which have improved properties with regard to the therapeutic range. In addition new pharmaceutical forms of administration are often developed with this goal. In this process the intention is in particular to avoid an undesired interaction with healthy cells/tissues.
The compounds according to the invention have shown no toxic effects whatsoever in vitro and in vivo up to the highest concentration and dose tested of 100 &mgr;g/ml and 100 mg/kg.
The compounds of formulae I and II are suitable for the treatment of (retro)viral infections in humans such as persistent generalized lymphoadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the full clinical picture of AIDS.
The inhibitory action on HI viruses (HIV 1 and HIV 1) which are responsible for the immune deficiency disease AIDS is of therapeutic interest. 3′-Azido-3′-deoxythymidine (DE-A-3608606) is today approved for the treatment of AIDS. However, toxic side-effects of 3′-azido-3′-deoxythymidine e.g. on bone marrow limit the use of this medicament. The compounds of the general formulae I and II do not have these disadvantages. They have an antiviral/antiretroviral action without being (cyto)toxic in pharmacologically relevant doses.
The compounds of the present invention and their pharmacological preparations can be used in combination with other pharmaceutical agents for the treatment and prophylaxis of the aforementioned infections. Examples of agents containing further pharmaceutical agents which can be used for the treatment and prophylaxis of HIV infections or diseases accompanying this illness are 3′-azido-3′-deoxythymidine, 2′,3′-dideoxy

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