Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1999-05-11
2001-06-05
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S091000, C514S071000, C514S211070, C514S213010, C514S298000, C530S330000, C530S331000, C540S485000, C540S523000, C546S205000, C548S400000, C548S409000, C548S452000, C548S567000
Reexamination Certificate
active
06242432
ABSTRACT:
The present invention relates to new products having an antithrombotic activity.
Cyclooxygenase (COX)-inhibiting anti-inflammatory products are known from previous patent applications in the name of the Applicant. See in particular the published patent applications WO 94/04484, WO 94/12463, WO 95/09831, WO95/30641. These patent applications referred to non-steroid anti-inflammatory products with a non-acid ending and to those with an acid ending mentioned as products known in the art.
Said products showed a much lower toxicity level compared to the reference products not containing group —ONO
2
.
WO 95 30641 discloses compounds endowed with COX inhabiting activity and endowed with antithrombotic and antihypertensive activity.
EP 637583 concerns 1-anloxy-3-alkylamino-2-propanol nitrate esters of the general formula:
wherein R
1
is —(CH
2
)
m
—Z —R
2
, m is 1 or 2, Z is —O— ether, —CONH amide or —COO— ester function and R
2
is a C
2-3
straight or branched chain alkyl having at least one nitroxy group. Said compounds are useful as drugs for the cardiovascular field.
WO 97 31896 discloses derivatives of formula:
wherein X is —CH
2
—, —O—, —S—; R
1
represents an alkanoyl group having one or more substituents. A represents alkylene or a group -B-D-E (where B and E may be the same or different and each represents a single bond or alkylene, and D represents cycloalkylene optionally substituted by aryl).
Said compounds have vasodilating and antianginal actions and are useful in the prophylaxis or treatment of angina pectoris.
The need for available products having an antithrombotic activity combined with lower toxicity in long term treatment was felt. In particular, the efficacy and safety of antithrombotic agents are closely related and research is aiming to find out new molecules with an increased therapeutic index, i.e. with improved efficacy and reduced toxicity (Goodman & Gilman: “The pharmacological basis of therapeutics”, Ed. J. Hardman, L. Limbrid, Page 1357, 1996).
It was unexpectedly and surprisingly found that the products of the invention as defined below are effective in inhibiting platelet aggregation induced by different kinds of stimuli, in particular collagen and thrombin, and at the same time exhibit high safety in general, in particular a high gastric safety, without causing lesions to the gastro-intestinal mucosa in the treated animals.
The results of the present invention are much more surprising considering that the new classes of products of the invention are not cyclooxigenase (COX) inhibiting products and, therefore, they cannot be drawn in any way from the products described in the known art, in particular in the above patents.
A subject of the present invention are the compounds, or their compositions, of the general formula:
A-(X
1
—NO
2
)
t
0
or their salts, for use as medicaments, in particular as antithrombotic agents since they are effective in inhibiting platelet aggregation, where:
t
o
is an integer equal to 1 or 2;
A=RN
o
where N
o
=(COX
u
)
t
- or COON
1
where t is an integer equal to zero or 1; u is an integer equal to 0 or 1;
X=O, NH, NR
1c
where R
1c
is a linear or branched alkyl having from 1 to 10 carbon atoms; N
1
is a linear or branched alkyl having from 1 to 10 carbon atoms or hydrogen;
R is chosen from the following groups:
*Group A)
where R
Ia
and R
IIa
are equal or different one from the other and are H or a linear or whenever possible branched alkyl having from 1 to 3 C atoms, preferably R
Ia
=R
IIa
=H; n
Ia
is an integer from 1 to 6 , preferably from 2 to 4; R
I
can be:
where N
2
has the same meaning as N
o
; at least one of the groups N
o
or N
2
having one free valence capable of binding to X
1
, (that is, t=1),
R
Ia
, R
IIa
, n
Ia
are defined in Ia;
N
3
is H, (CH
3
)
2
CH—CH—OCOCH
2
CH
3
, or a free valence to which X
1
binds (that is, N
3
is absent);
R
Ib
is chosen from;
N
2
is as above defined, where at least one of the groups N
3
or N
2
has a free valence capable of binding to X
1
(when it is N
2
, t=1);
N
2
, t=1);
Ic) where t=1
where N
o
is as above defined where t=1, i.e. it has a free valence capable of binding to X
1
;
R
Ic
is chosen from H, —COCH
3
, or
where N
2
is as defined, and at least one of the groups N
2
has a free valence (t=1) capable of binding to X
1
;
*Group B
where t=1 and u=0; when Ic/.R
IC
is H or COCH
3
, X cannot be NH.
where R
Ia
, R
IIa
are as defined in Ia);
R
IIb
has the meaning of R
Ia
;
R
BA
is chosen from:
where, in group B), N
2
is as above defined and at least one of the N
2
groups has a free valence capable of binding to X
1
, (that is, at least one N
2
substituent has t=1;
X
1
is a bivalent connecting bridge chosen from the following:
YO where Y is a linear or whenever possible branched C
1
-C
20
alkylene, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms;
Y
1
chosen from
where n
3
is an integer from 0 to 3;
where nf′ is an integer from 1 to 6, preferably from 2 to 4;
where R
1f
=H, CH
3
and nf is an integer from 1 to 6; preferably from 2 to 4.
The compounds which may be mentioned, and which are the preferred compounds, are those listed below where R can be obtained by the processes known in the art.
For example, the compounds and processes described in the Merck Index, Ed. 12 of 1996, an be mentioned as precursors and related processes. The precursors (according to the Merck nomenclature) as those shown below, where the various substituents shown in the formulas of group A) and group B) are as defined in the compounds listed: Alacepril, Benazepril, Captopril, Ceronapril, Cilazapril, Delapril, Enalapril, Enalaprilat Fosinapril, Imidapril, Lisinopril, Quinapril, Ramipril, Spirapril, Temocapril, Trandolapril, Moveltilpril, Perindopril, Befunolol, Betaxolol, Bupranolol, Carteolol, Levobunolol, Metipranolol, Timolol, Oxprenolol, Mepindolol, Atenolol, Labetalol.
The connecting bridges X
1
as above defined can be obtained using the methods from the known art or modifying the known methods by introducing X
1
bridges when these are different from the connecting bridges described in the mentioned patents by processes known in the art. In general, the connection between A and X
1
is, as seen, of an ester or amide type (NH or NR
1c
, as defined in X). Any synthetic route well known for forming these bonds can be used.
In the case of esters, the most direct synthetic route includes reaction of acyl chlorides A-CO—Cl, or A-(CO—Cl)
2
, in halogen alcohols of the type HO—Y
a
—Cl, HO—Y
a
—I, where Y
a
is equal to Y or Y
1
as above defined without the oxygen atom —O—, in experimental conditions which are part of the known art.
The reaction products of formula A-CO—O—Y
a
—Cl(Br,I) can also be obtained by reacting the sodium or potassium salts of said acids A-CO—OH with di-halogen derivatives of the general formula Y
a
CL
2
, Y
a
Br
2
or Y
a
I
2
.
The reaction products are converted into the final products by reaction with AgNO
3
in acetonitrile according to processes known in the prior art.
The general scheme is as follows:
A-CO—Cl=HO—Y
a
—Br - - - >A-CO—O—Y
a
—Br=AgNO
3
- - - >A-X
1
NO
2
where X
1
=Y
a
O.
the general scheme can also be as follows:
A-CO—ONa=Br
2
Y
a
- - - >A-CO—O—Y
a
—Br=AgNO
3
- - - >A-X
1
NO
2
where X
1
=Y
a
O.
In the case of amides, the synthetic sequence includes reaction of the same acyl chlorides A-CO—Cl with amino alcohols of the general formula NH
2
—Y
a
—OH or NHR
1c
—Y
a
—OH to give amides of the general formula:
A-CO—NH—Y
a
—OH or A-CO—NR
1c
—Y
a
OH
in accordance with known methods.
Reaction of these amides with halogenating agents such as, for example, PCl
5
, PBr
3
, SOCl
2
, etc, leads to halogen derivatives of the general formula:
A-CO—NH—Y
a
—Br(Cl) and A-CO—NR
1c
13
Y
a
—Br(Cl).
By reaction with AgNO
3
in acetonitrile according to known literature methods said latter products lead
Arent Fox Kintner Plotkin & Kahn
Balasubramanian Venkataraman
Nicox S.A.
Shah Mukund J.
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