Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-11
2004-11-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S228800, C514S315000, C514S345000, C514S529000, C514S765000, C514S769000, C549S200000, C549S263000, C549S273000, C549S293000, C549S356000, C549S425000, C549S427000, C549S426000
Reexamination Certificate
active
06818638
ABSTRACT:
The present invention relates to mevinolin derivatives, a process for their production, their use as a pharmaceutical and pharmaceutical preparations containing them. More particularly the present invention provides a compound of formula I
wherein
each of a - - - b and &agr; - - - &bgr; independently, is either a single bond or a double bond;
R
1
is
wherein R
a
is H; C
1-6
alkyl optionally substituted by OH or C
1-4
alkoxy; C
2-6
alkenyl; or aryl-C
1-4
alkyl;
R
2
is OH; —O—CO—R
5
wherein R
5
is C
1-8
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl-C
1-4
alkyl, aryl or aryl-C
1-4
alkyl; or —O—R
6
wherein R
6
is the residue of an &agr;-amino-acid attached to O through its carbonyl residue or —CHR
7
—COR
5
wherein R
7
is H, C
1-4
alkyl, hetero C
1-4
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl-C
1-4
alkyl, aryl or aryl-C
1-4
alkyl and R
8
is OH, C
1-4
alkoxy or NR
9
R
10
wherein each of R
9
and R
10
independently is H, C
1
alkyl or R
9
and R
10
form together with the nitrogen to which they are bound, a heteroaryl group;
R
3
is a substituted lactam, piperidyl, linear amino alcohol or cyclic carbamate, or a residue of formula (i)
wherein
R
13
is OH; C
1-6
alkoxy; —O—CO—C
1-6
alkyl; or —O—CO—NHC
1
alkyl;
R
14
is OH; C
1-4
alkoxy; C
1-4
alkyl; C
1-4
alkoxy-carbonyl-C
1-4
alkoxy; hydroxy-C
1-5
alkoxy; C
1-4
alkoxy-C
1-5
alkoxy; C
1-4
alkoxy-carbonyl-C
1-4
alkyl; or NR
9a
R
10a
-C
1-5
alkoxy wherein each of R
9a
and R
10a
independently has one of the significances given for R
9
and R
10
;
R
15
is H or C
1-4
alkyl; and
R
16
is CONR
17
R
18
wherein one of R
17
and R
18
is H and the other is C
1-6
alkyl, hydroxy-C
1-6
alkyl, C
3-7
cycloalkyl-C
1-4
alkyl or aryl-C
1-4
alkyl; or C
1-6
alkoxy-carbonyl; each of a - - - b and &agr; - - - &bgr; being a single bond when each of R
13
or R
14
is OH; and
R
4
is H or OR
19
wherein R
19
is C
1-6
alkyl, hydroxy-C
1-6
alkyl, C
1-4
alkoxy-C
1-6
alkyl, aryl-C
1-4
alkyl or C
1-4
alkoxycarbonyl-C
1-4
alkyl,
and wherever “aryl” appears as is or in the significances of “aryl-C
1-4
alkyl” in the above definition, it is “phenyl” or “naphthyl” optionally substituted by halogen, OH, NR
11
R
12
, COOH, CF
3
, C
1-4
alkoxy, C
1-4
alkyl, hydroxy-C
1-4
alkyl, hydroxy-C
1
alkoxy, C
1-4
alkoxy-carbonyl, cyano or CONR
11
R
12
, each of R
1
, and R
12
independently being H, C
1-4
alkyl, phenyl, naphthyl, phenyl-C
1-4
alkyl or naphthyl-C
1-4
alkyl or R
11
and R
12
together with the nitrogen to which they are bound forming heteroaryl; and wherever “heteroaryl” appears, it is a 5- or 6-membered heterocyclic residue optionally fused to a benzene ring; in free form or in salt form.
Alkyl groups or alkyl moieties may be branched or straight chain. Cycloalkyl groups or moieties are preferably cyclopentyl or cyclohexyl. Heteroalkyl includes e.g. halogenated alkyl such as CF
3
. Polyhydroxy-C
1-4
alkyl may comprise up to 6 hydroxy groups.
Preferably the phenyl or naphthyl moiety in aryl or aryl-C
1-4
alkyl, when substituted, bears up to 3 substituents as disclosed above, more preferably selected from C
1-4
alkoxy, e.g. methoxy or ethoxy, hydroxy-C
1-4
alkoxy, hydroxy-C
1-4
alkyl and OH. When the phenyl moiety is disubstituted, the 2 substitutents are preferably in positions meta and para. Aryl-C
1-4
alkyl is preferably benzyl, phenethyl or naphthyl-CH
2
—, the phenyl or naphthyl moiety being optionally substituted as indicated above.
Examples of heteroaryl include pyrrolyl, imidazolyl, turyl, thienyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, pyridyl, indolyl or quinolyl. Heteroaryl as formed by R
5
and R
10
together with the nitrogen to which they are attached, may comprise a further heteroatom, e.g. O or N, and is preferably pyrrolidinyl, piperidyl, piperazinyl or morpholino. In heteroaryl-C
1-4
alkyl, the alkyl moiety preferably is C
1
or C
2
alkyl.
The significances given above for “aryl” and “heteroaryl” also applies to the radicals of formulae (a), (b), (c
1
) or (c
2
) hereinafter.
When R
6
is the residue of an &agr;-amino acid, it may be the residue of a natural or unnatural &agr;-amino acid residue, e.g. Ala, Leu, Ile, Val, Pro, wherein the terminal amino group may be substituted or unsubstituted, e.g. by an amino protecting group.
When R
3
is a substituted lactam residue, it is preferably a 6-membered ring wherein the nitrogen of the lactam may be substituted and/or comprising a further substituent on the ring, e.g. on the carbon atom opposite to the nitrogen. Preferably the lactam residue is disubstituted. A suitable example of a substituted lactam as R
3
includes e.g. a radical of formula (a)
wherein
R
30
is C
1-8
alkyl; C
3-7
cycloalkyl; aryl; C
3-7
cycloalkyl-C
1-4
alkyl; aryl-C
1-4
alkyl; heteroaryl; or heteroaryl-C
1-4
alkyl;
R
31
is OH; C
1-4
alkoxy; C
1-4
alkyl; C
1-4
alkoxy-carbonyl-C
1-4
alkoxy; hydroxy-C
1-5
alkoxy; C
1-4
alkoxy-C
1-5
alkoxy; C
1-4
alkoxy-carbonyl-C
1-4
alkyl; amino-C
1-4
alkoxy; HOOC—C
1-4
alkoxy; HOOC—C
1-4
alkyl; or NR
9a
R
10a
-C
1-5
alkoxy wherein each of R
9a
and R
10a
independently has one of the significances given for R
9
and R
10
.
When R
3
is a substituted piperidyl residue, the nitrogen of the piperidyl may be substituted and/or a further substituent may be present on the ring, e.g. on the carbon atom opposite to the nitrogen. Preferably the piperidyl residue is disubstituted. A suitable example of a substituted piperidyl residue includes e.g. a radical of formula (b)
wherein
R
40
has one of the significances given for R
30
; and
R
41
has one of the significances given for R
31
or is —O—CO—C
1-8
alkyl.
When R
3
is a substituted amino alcohol residue, the amino group thereof may be monosubstituted, e.g. by a substituent such as aryl-C
1-4
alkyl or aryl-C
1-4
alkyl-carbonyl, and/or a further substituent may be present on the chain, e.g. on the carbon atom adjacent to the alcohol or amino group. Cyclisation of the substituted amino alcohol residue leads to a corresponding substituted cyclic carbamate. A suitable example of a substituted amino alcohol and of the corresponding substituted cyclic carbamate includes e.g. a radical of formula (c
1
) or (c
2
)
wherein
either each of X and Y is H or X and Y form together
each of R
50
, independently is H; C
1-8
alkyl; C
3-7
cycloalkyl; aryl; C
3-7
cycloalkyl-C
1-4
alkyl; aryl-C
1-4
alkyl; heteroaryl; heteroaryl-C
1-4
alkyl; C
1-4
alkylcarbonyl; aryl-carbonyl; heteroaryl-carbonyl; aryl-C
1-4
alkyl-carbonyl or heteroaryl-C
1-4
alkyl-carbonyl, and
each of R
51
, independently is H; C
1-4
alkyl; hydroxy-C
1-4
alkyl; amino-C
1-4
alkyl; C
1-4
alkoxy-C
1-4
alkyl; C
1-4
alkoxy-carbonyl-C
1-4
alkyl wherein C
1-4
alkoxy is optionally substituted by amino, C
1-4
alkyl-amino or di-(C
1-4
alkyl)amino; HOOC—C
1-4
alkyl; or R
23
R
24
N—CO—C
1-4
alkyl wherein R
23
is H, C
1-4
alkyl, hydroxy-C
1-4
alkyl, polyhydroxy-C
1-8
alkyl, heteroaryl, heteroaryl-C
1-4
alkyl, amino-C
1-4
alkyl, C
1-4
alkylamino-C
1-4
alkyl, di-(C
1-4
alkyl)amino-C
1-4
alkyl or aryl-C
1-4
alkyl and R
24
is H, C
1-4
alkyl or hydroxy-C
1-4
alkyl, at least one of R
50
and R
51
being other than H.
Preferred compounds of formula I are those wherein R
3
is substituted lactam, substituted linear amino alcohol, substituted cyclic carbamate, preferably substituted lactam or substituted cyclic carbamate, e.g. as disclosed above, more preferably a radical of formula (a) or (c
1
) or (c
2
) wherein X and Y are —CO—.
In the compounds of formula I, the following significances are preferred individually or in any sub-combination:
1. R
1
is H or CH
3
, preferably CH
3
;
2. R
2
is —O—CO—R
5
, preferably wherein R
5
is C
4
alkyl, particularly —CH(CH
3
)—CH
2
—CH
3
, —CH(CH
2
—CH
2
—CH
3
)
2
, —CH(CH
2
—CH
3
)
2
, —C(CH
3
)
2
—CH
2
—CH
3
—CH
2
—CH
3
)—CH
2
—CH
2
—CH
3
.
3. a - - - b is a double bond;
4. &agr; - - - &bgr; is a double bond;
5. R
4
is H;
6. R
3
is a radical of formula (i);
7. R
16
is CO—NR
17
R
18
; preferably one of R
17
and R
18
is H;
8. Each of R
13
and R
1-4
is OH and each of a - - - b and &agr; - - - &bgr; is a single bond;
9. Each of R
13
and R
1-4
is other than
Baenteli Rolf
Bauer Wilfried
Cottens Sylvain
Ehrhardt Claus
Hommel Ulrich
Novartis AG
Patel Sudhaker B.
Raymond Richard L.
Savitsky Thomas R.
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