Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1999-07-23
2001-06-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C540S145000
Reexamination Certificate
active
06251367
ABSTRACT:
The invention relates to the subject that is characterized in the claims, i.e., paramagnetic 3-, 8-substituted deuteroporphyrin derivatives, pharmaceutical agents that contain the latter, process for their production, and their use for MR imaging of necrosis and infarction.
Detecting, locating, and monitoring necroses or infarctions is an important area in medicine. Thus, myocardial infarction is not a stationary process, but rather a dynamic process, which extends over a prolonged period—weeks to months. Infarction runs in phases, which are not strictly separate from one another but rather overlap. The first phase, the development of myocardial infarction, comprises the 24 hours after the infarction, during which the destruction spreads like a wave from the subendocardium to the myocardium. The second phase, the already existing infarction, comprises the stabilization of the area in which fiber formation (fibrosis) takes place as a healing process. The third phase, the healed infarction, begins after all destroyed tissue is replaced by fibrous scar tissue. During this period, extensive restructuring takes place.
Up until now, no specific and reliable process has been known that makes it possible to determine the current phase of a myocardial infarction in a live patient. To evaluate a myocardial infarction, it is of decisive importance to know how large the proportion of the tissue is that is extinct (lost) in the infarction and at what point the loss has taken place since the type of treatment depends on this knowledge. Infarctions take place not only in the myocardium but also in other tissues, especially in the brain.
While the infarction can be healed to a certain extent, in the case of a necrosis, locally limited tissue death, only the harmful sequelae for the residual organism can be prevented or at least mitigated. Necroses can occur in many ways: from injuries, chemicals, oxygen deficiency, or radiation.
As in the case of infarction, knowing the extent and type of necrosis is important for subsequent medical treatment. Attempts have thus already been made to improve the detection and locating of infarctions and necroses by using contrast media in the case of noninvasive processes such as scintigraphy or MRI. In literature, attempts to use porphyrins for necrosis imaging take up a good deal of space. The results that have been achieved, however, paint a contradictory picture. Winkelman and Hayes in Nature, 200, 903 (1967) describe the fact that Mn-5,10,15,20-tetrakis (4-sulfonatophenyl)-porphyrin (TPPS) accumulates selectively in the necrotic portion of a tumor. Lyon et al., Magn. Res. Med. 4, 24 (1987), however, observed that Mn-TPPS is distributed in the body, specifically in the kidney, liver, tumor and only in a small proportion in the muscles. In this case, it is advantageous for the concentration in the tumor to reach its maximum only on the fourth day, and this occurred only after the authors had increased the dose to 0.2 mmol/kg. The authors therefore also speak of a clearly nonspecific uptake of TPPS into the tumor.
Bockhorst et al. again report in Acta Neurochir. 1994 [Suppl.] 60, 347 that MnTPPS selectively binds to tumor cells. Foster et al., J. Nucl. Med. 26, 756 (1985) in turn found that In-111 5,10,15,20-tetrakis (4-N-methyl-pyridinium)-porphyrin (TMPyP) does not accumulate in the necrotic part, but rather in the living edge layers.
This does not necessarily indicate that a porphyrin-type-tissue-dependent interaction exists.
In Circulation, Vol. 90, No. 4, 1994, Part 2, Page 1468, Abstr. No. 2512, Ni et al. report that they can readily visualize infarction areas with an Mn-tetraphenyl-porphyrin (Mn-TTP) and a Gd-mesoporphyrin (Gd-MP).
Both substances are the subject of Application WO 95/31219.
In the case of scintigraphic processes, the dose that is used is in the nanomol range. The compatibility of the substances therefore plays only a subordinate role. With MR imaging, however, the dose is in the millimole range. Here, compatibility plays a quite decisive role.
The small acute compatibilities (LD50) that are determined for MnTPP or MnTPPS rule out their use in humans.
In addition, porphyrins—such as, e.g., Gd-mesoporphyrin—tend to be deposited in the skin, which results in photosensitization. This sensitization can last for days or even weeks. In the case of scintigraphic processes, this effect would be unimportant because of the low dose. Broad use of scintigraphic processes, however, is contraindicated owing to the fact that the resolution of a gamma camera is very much lower than that which can be achieved with MR imaging.
For MR imaging of myocardial infarction, the Gd-complexes of DTPA were also used (K. Bockhorst et al., Acta Neurochir. (1997) Suppl., 60:347-349); De Roos et al., Radiology 1989; 172:717-720) and its bis(methylamide) (M. Saeed et al., Radiology, 1992; 182:675-683). It turned out that both contrast media make it possible to differentiate between healthy and infarcted tissue only in a narrow time window. Comparable results were also obtained with the manganese compound of DTPA (Immunomedics, WO 94/22490) and DPDP (Radiology 1989; 172:59-64).
Weissleder et al., Radiology 1992; 182:675-683, who coupled antimyosin to iron oxides (MION), achieved a considerable improvement. Owing to its specific structure, this contrast medium is not suitable for necrosis imaging.
There is therefore an urgent need to have compounds for MR imaging of infarction and necrosis that:
are very well-tolerated,
are not phototoxic,
are chemically stable,
are completely excreted,
accumulate in necroses,
are not concentrated in the skin,
have a high relaxivity,
exhibit high water solubility,
provide a wide time window for measurement,
make possible good differentiation between healthy and necrotic/infarcted tissue.
It has been found, surprisingly enough, that porphyrin complexes that consist of a ligand of general formula I
and at least one ion of an element of atomic numbers 20-32, 37-39, 42-51 or 57-83, in which
M stands for a paramagnetic ion,
R
1
stands for a hydrogen atom, for a straight-chain C
1
-C
6
alkyl radical, a C
7
-C
12
aralkyl radical, or for a group OR′ in which
R′ is a hydrogen atom or a C
1
-C
3
alkyl radical,
R
2
stands for R
3
, a group —CO—Z or a group—(NH)
o
—(A)
q
—NH—D, in which
Z is a group —OL, with L in the meaning of an inorganic or organic cation or a C
1
-C
4
alkyl radical,
A means a phenylenoxy group or a C
1
-C
12
alkylene group that is optionally interrupted by one or more oxygen atoms or a C
7
-C
12
aralkylene group,
o and q, independently of one another, mean numbers 0 or 1, and
D means a hydrogen atom or a group —CO—A—(COOL)
o
—(H)
m
, with m equal to 0 or 1 and provided that the sum of m and o is equal to 1,
R
3
stands for a group —(C=Q)(NR
4
)
o
—(A)
q
—(NR
5
)—K, in which Q stands for an oxygen atom or for two hydrogen atoms,
R
4
means a group —(A)
q
—H, and
K means a complexing agent of general formula (IIa), (IIb), (IIc), (IId) (IIe), or (IIf), whereby if K is a complexing agent of formula (IIa), R
5
has the same meaning as R
4
, and if K is a complexing agent of formula (IIb), (IIc), (IId), (IIe), or (IIf), R
5
has the same meaning as D,
provided that a direct oxygen-nitrogen bond is not allowed,
and K stands for a complexing agent of general formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf)
in which
q has the above-indicated meaning,
A′ has the meaning that is indicated for A,
R
6
stands for a hydrogen atom, a straight-chain or branched C
1
-C
7
alkyl group, a phenyl or benzyl group,
A
2
stands for a phenylene, —CH
2
—NHCO—CH
2
—CH(CH
2
COOH)—C
6
H
4
-&bgr;-, —C
6
H
4
—O—(CH
2
)
0-5
-&bgr;-, —C
6
H
4
—(OCH
2
CH
2
)
0-1
—N (CH
2
COOH)—CH
2
-&bgr;-group or a C
1
-C
12
alkylene or C
7
-C
12
alkylene group that is optionally interrupted by one or more oxygen atoms, 1 to 3 —NHCO or 1 to 3 —CONH groups and/or substituted with 1 to 3 —(CH
2
)
0-5
COOH groups, whereby &bgr; stands for the binding site to X,
X stands for a —CO— or NHCS group and
L
1
, L
2
, L
3
and L
4
, in
Niedballa Ulrich
Platzek Johannes
Raduechel Bernd
Millen White Zelano & Branigan P.C.
Raymond Richard L.
Schering Aktiengesellschaft
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