Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-25
2003-12-23
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S125000, C560S037000, C560S038000, C564S191000
Reexamination Certificate
active
06667314
ABSTRACT:
This invention relates to tropane derivatives useful in the treatment of a variety of disorders, including those in which the modulation of CCR5 receptors is implicated. More particularly, the present invention relates to 3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]octane derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. Disorders that may be treated or prevented by the present derivatives include HIV and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS), and inflammatory diseases.
The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV-1 and genetically related retroviruses. The name “chemokine”, is a contraction of “chemotactic cytokines”. The chemokines comprise a large family of proteins which have in common important structural features and which have the ability to attract leukocytes. As leukocyte chemotactic factors, chemokines play an indispensable role in the attraction of leukocytes to various tissues of the body, a process which is essential for both inflammation and the body's response to infection. Because chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents which are active in modulating, preferably antagonizing, the activity of chemokines and their receptors, are useful in the therapeutic treatment of such inflammatory and infectious diseases.
The chemokine receptor CCR5 is of particular importance in the context of treating inflammatory and infectious diseases. CCR5 is a receptor for chemokines, especially for the macrophage inflammatory proteins (MIP) designated MIP-1&agr; and MIP-1&bgr;, and for a protein which is regulated upon activation and is normal T-cell expressed and secreted (RANTES).
There has been a substantial investigation of different classes of modulators of chemokine receptor activity, especially that of the CCR5 chemokine receptor, for example, WO 98/25617 relates to substituted aryl piperazines as modulators of chemokine receptor activity.
The present compounds are generally disclosed by WO 00/38680 but none is specifically exemplified therein.
According to a first aspect of the present invention, there is provided a compound of formula (I),
wherein R
1
is C
3-6
cycloalkyl optionally substituted by one or more fluorine atoms, or C
1-6
alkyl optionally substituted by one or more fluorine atoms, or C
3-6
cycloalkylmethyl optionally ring-substituted by one or more fluorine atoms; and
R
2
is phenyl optionally substituted by one or more fluorine atoms:
or a pharmaceutically acceptable salt or solvate thereof.
According to a second aspect of the present invention, there is provided a compound of formula (IA),
wherein R
1
represents either C
3-6
cycloalkyl optionally substituted by one or more fluorine atoms, or C
1-6
alkyl optionally substituted by one or more fluorine atoms, or a pharmaceutically acceptable salt or solvate thereof.
“C
1-6
alkyl” in the definition of R
1
includes straight-chain and branched groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. “C
3-6
cycloalkyl” means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The compounds of formula (I) contain a basic centre and suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, camsylate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts. For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977.
The pharmaceutically acceptable solvates of the compounds of the formula (I) or salts thereof include the hydrates thereof.
Also included within the present scope of the compounds of the formula (I) are polymorphs thereof.
A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by; reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
The invention also includes isotopically labelled compounds of the formula (I).
Preferably, R
1
is either C
4-6
cycloalkyl optionally substituted by one or two fluorine atoms, or C
1-4
alkyl optionally substituted by from one to three fluorine atoms.
Preferably, R
1
is either cyclobutyl, cyclopentyl, 4,4-difluorocyclohexyl or 3,3,3-trifluoropropyl.
Preferably, R
2
is phenyl optionally substituted by 1 or 2 fluorine atom(s).
Preferably, R
2
is phenyl or monofluorophenyl.
Preferably, R
2
is phenyl or 3-fluorophenyl.
Preferred compounds of the formula (I) include
N-{(1S)-3-[3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclobutanecarboxamide;
N-{(1S)-3-[3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclopentanecarboxamide;
N-{(1S)-3-[3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}-4,4,4-trifluorobutanamide;
N-{(1S)-3-[3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}-4,4-difluorocyclohexanecarboxamide; and
N-{(1S)-3-[3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}-4,4-difluorocyclohexanecarboxamide: or a pharmaceutically acceptable salt or solvate of any thereof.
The compounds of the formula (I) may be prepared by the following general methods in which R
1
and R
2
are as previously defined for a compound of the formula (I) unless otherwise stated.
1. A compound of the formula (I) may be prepared by reacting a compound of formula:
with a compound of formula:
R
1
CO
2
H (III)
under conventional coupling conditions.
The reaction is preferably carried out in the presence of a suitable coupling agent (for example, N-benzyl-N′-cyclohexylcarbodiimide (which may be polymer-bound), or hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide), at about room temperature, in a solvent that does not adversely affect the reaction, for example, dichloromethane. Further suitable coupling conditions are described in Method 2 below.
The compounds of formula (III) are either known or are prepared using conventional techniques.
The compounds of the formula (II) may be prepared as shown in Scheme 1 below.
2. The compounds of the formula (I) may be prepared as shown in Scheme 1.
wherein P is a suitable protecting group such as t-butyloxycarbonyl, benzyl or benzyloxycarbonyl and the compounds of the formula (II) and (VII) are in the exo form. In a typical procedure, where P is t-butyloxycarbonyl, an amine of the formula (IV) is reacted with d
Perros Manoussos
Price David Anthony
Stammen Blanda Luzia Christa
Wood Anthony
Huang Evelyn Mei
Hutchinson Keith D.
Pfizer Inc.
Richardson Peter
Zielinski Bryan C.
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