Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
1999-02-01
2002-09-17
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C514S018700, C514S019300
Reexamination Certificate
active
06451973
ABSTRACT:
The invention relates to heterocyclic anilinobenzylazahexane derivatives which can be employed as substrate isosters of retroviral aspartate proteases, to salts thereof, to processes for preparing these compounds and their salts, to pharmaceutical preparations which comprise these compounds or salts thereof, and to the use of these compounds or of salts thereof (either alone or in combination with other active compounds which are effective against retroviruses) for the therapeutic or diagnostic treatment of a human or animal body or for producing pharmaceutical preparations.
BACKGROUND TO THE INVENTION
According to UN estimates, approximately 28 million people are infected with the “human immunodeficiency virus” i.e. HIV-1 or HIV-2. In infected patients, the disorder leads, by way of preliminary stages such as ARDS, and with very few exceptions, to a manifest disease of the immune system which is termed “acquired immunodeficiency syndrome” or AIDS. In what is by far the overwhelming majority of cases, this disease leads, sooner or later, to the death of the infected patient.
For treating retroviral diseases such as AIDS, use has hitherto been made primarily of inhibitors of reverse transcriptase, an enzyme which is active in converting retroviral RNA into DNA, such as 3′-azido-3′-deoxythymidine (AZT) or dideoxyinosine (DDI), and also trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-&bgr;-D-ribo-furanosyl-1,2,4-triazole-3-carboxamide and dideoxycytidine, and also adriamycin. In addition to this, there have been experiments to introduce the T4 cell receptor, which is present in the human body on particular cells of the immune system and is responsible for anchoring and introducing infectious virus particles into these cells. and consequently for their ability to infect, into the body, for example as a recombinant molecule or as a molecular fragment. This would thereby block viral binding sites so that the virions were no longer able to bind to the cells. Use is also being made of compounds, such as polymannoacetate, which employ other means to prevent the virus penetrating the cell membrane.
Saquinavir [N-tert-butyldecahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-2-quinolylcarbonyl-L-asparagnyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (Ro 31-8959); Hoffmann LaRoche] was the first inhibitor of so-called retroviral aspartate protease to be authorized for controlling the infection. Others have followed since then (Indinavir from Merck and Ritonavir from Abbott).
In addition, development is proceeding on a number of other inhibitors of retroviral aspartate protease, which is an enzyme whose function can be characterized as follows:
In the AIDS viruses, i.e. HIV-1 and HIV-2, and in other retroviruses, for example corresponding viruses in cats (FIV) and monkeys (SIV), an aspartate protease, such as the HIV protease, effects proteolytic maturation of the viral core proteins, for example. No infectious viral particles can be formed without this proteolytic maturation. The central role of the said aspartate proteases, such as HIV-1 protease or HIV-2 protease, in virus maturation, and experimental results obtained, for example, with infected cell cultures, have made it seem likely that effective prevention of the maturation step which is brought about by this protease would prevent the assembly of mature virions in vivo. As a consequence, inhibitors of this protease can be employed therapeutically.
The object of the present invention is to make available a novel type of compound which is endowed, in particular, with a pronounced inhibitory effect on viral multiplication in cells, with a high degree of antiviral activity against a large number of viral strains including those which are resistant to known compounds such as Saquinavir, Ritonavir and Indinavir, and with particularly favorable pharmacological properties, for example good pharmacokinetics, such as high bioavailability and/or high blood levels, and/or high selectivity.
EP 0 604 368 mentions a genus of compounds with HIV protease inhibiting activity—however, neither are the compounds of the present invention mentioned therein, nor are there any hints to the advantageous properties of the compounds of the formula I in the present disclosure.
COMPLETE DESCRIPTION OF THE INVENTION
The azahexane derivatives according to the invention are compounds of the formula I,
in which
R
1
and R
2
are, independently of each other, lower alkyl or lower alkoxy-lower alkyl;
R
3
and R
4
are, independently of each other, sec-lower alkyl or tert-lower alkyl;
R
5
is phenyl or cyclohexyl; and
R
6
and R
7
are, independently of each other, lower alkyl, or, together with the linking nitrogen atom, pyrrolidino, piperidino, 4-lower alkylpiperidino, 1,2,4-triazol-1-yl or 1,2,4-triazol-4-yl;
or a salt thereof, provided that at least one salt-forming group is present.
These compounds possess unexpectedly good, and surprisingly positive, pharmacological properties, as explained in detail below, and are relatively simple to synthesize.
Within the context of the present disclosure, the general terms which are used above and in that which follows preferably have the following meanings unless otherwise indicated:
The prefix “lower” designates a radical having not more than 7, in particular not more than 4, carbon atoms, with it being possible for the radicals concerned to be unbranched or to be branched once or more than once.
Lower alkyl and C
1
-C
4
alkyl are, in particular, tert-butyl, sec-butyl, iso-butyl, n-butyl, isopropyl, n-propyl, ethyl or, in particular, methyl.
Insofar as compounds, salts and the like are referred to in the plural, this also always means one compound, one salt or the like.
Any asymmetric carbon atoms which may be present, for example the carbon atoms which are linked to the radicals R
3
and R
4
, can be present in the (R), (S) or (R,S) configuration, preferably in the (R) or (S) configuration, with the (S) configuration being particularly preferred in the case of the carbon atoms in compounds of the formula I which carry the radical R
3
and/or the radical R
5
. Consequently, the present compounds can exist as isomeric mixtures or as pure isomers, preferably as an enantiomerically pure diastereomer.
Lower alkoxy-lower alkyl is preferably C
1
-C
4
alkoxy-lower alkyl, in which the alkyl radical can be branched or unbranched, and is, in particular, ethoxyethyl or methoxyethyl.
Sec-lower alkyl or tert-iower alkyl is, in particular, sec-butyl, tert-butyl or isopropyl.
Pyrrolidino is pyrrolidin-1-yl. Piperidino is piperidin-1-yl. 4-Lower alkylpiperidino is, in particular, N-methylpiperidin-4-yl.
Preferably, the compounds of the formula I have the formula Ia,
in which the radicals are as defined above or below.
Salts are first and foremost the pharmaceutically utilizable salts of compounds of the formula I.
These salts are formed, for example, from compounds of the formula I having a basic p-R
6
R
7
N—(C
6
H
5
)—CH
2
-carrying nitrogen atom as acid addition salts of strong acids, with strong acids preferably being understood to be inorganic acids, for example hydrohalic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or strong organic sulfonic, sulfo or phospho acids, or N-substituted sulfamic acids (preferably: pKa<1). When basic heterocyclyl radicals, such as piperidino or 4-lower alkylpiperidino, are present, other salts can exist, depending on the base strength, which the skilled person can readily estimate or find out. These salts include, in particular, acid addition salts with organic or inorganic acids, in particular the pharmaceutically utilizable salts. Examples of suitable inorganic acids are, depending on the base strength of the corresponding compound of the formula I, hydrohalic acids, such as hydrochloric acid; sulfuric acid; or phosphoric acid. Examples of suitable organic acids are carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, gly
Bold Guido
Capraro Hans-Georg
Fässler Alexander
Lang Marc
Low Christopher S. F.
Lukton David
Novatis AG
LandOfFree
Anilinopeptide derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Anilinopeptide derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Anilinopeptide derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2858131