PT80841B - Process for the preparation of compounds for site-enhanced delivery of radionuclides and of chelating agents useful therefor - Google Patents

Abstract

A dihydropyridine <SIGN> pyridinium salt type of redox, or chemical, delivery system for the site-specific and/or site-enhanced delivery of a radionuclide to the brain. A chelating agent capable of chelating with a radionuclide and having a reactive hydroxyl, carboxyl, amino, amide or imide group is coupled to a carrier moiety comprising a dihydropyridine <SIGN> pyridinium salt nucleus and then complexed with a radionuclide to provide a new radionuclide pharmaceutical that, in its lipoidal dihydropyridine form, penetrates the blood-brain barrier ("BBB") and allows increased levels of radionuclide concentration in the brain, particularly since oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt retards elimination from the brain while elimination from the general circulation is accelerated. This radionuclide delivery system is well suited for use in scintigraphy and similar radiographic techniques.

Description

DETAILED DESCRIPTION OF THE INVENTION:

The following definitions apply:

The term "drug" used in the text means any substance intended for use in the diagnosis, cure, relief, treatment or prevention of the disease in man or other animals.

The term "lipoidal" refers to a portion of the carrier that is lipid or lipophilic soluble.

The term "pharmaceutically acceptable non-toxic salts" generally comprises non-toxic salts of the products of the invention, of the general formula II or III, as defined above, which are formed with inorganic or organic non-toxic, acceptable acids in pharmacy, of the general formula EX. For example, the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, azetic and the like, and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic acids , lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicylic, sulfamylic, fumaric, methanesulfonic,

14

toluenesulfonic acid and the like. The expression 'pharmacokinetic or pharmacokinetically acceptable arachidonic acid' used in the text, for example in connection with the general formulas I and IV defined above, is intended to include acid anions of the general formula HX.

It should be considered, from the foregoing, that uir. compound of formula III may be administered in the form of the free base or in the form of a non-toxic pharmaceutically acceptable salt thereof, i.e. a salt which may be represented by the general formula,

DHC .7 _and ΉΧ

in which h, OCH3, and HX has the meaning defined above

and which, without taking into account the actual form in which the compound is administered, will be converted, in vivo, into a quaternary salt of general formula IV, the anion being represented by the symbol X ^- present "in vivo". There is no need for the anion to be introduced as part of the compound administered. In fact, even when the compound of formula III is used in its salt form, the anion of the compound of formula IV in vivo is not necessarily the same as that present in the compound of formula III. In fact, the exact identity of the anionic moiety of the compound of formula IV is not important for the in vivo transformation of the compound of formula III in compound IV.

The expression "at least one amino, carboxyl, hydroxy, amide or imide reactive functional group" used in the text, the reactive functional groups mentioned have the following meanings

two

; 30500:

yl

The term "amino" means any primary or secondary amino group, i.e., a -HH 2 group. or a group of formula -B HB, in which B represents, typically a

or a portion of the chelating agent residue itself. The secondary amino group is also represented herein by the formula -1H-, especially since the exact identity of the portion represented by the symbol R in the general formula -NHR is not important,

so as not to prevent the formation of the chelating agent residue and its attachment to the vehicle moiety or otherwise interfere with the objects of the present invention.

The term "carboxyl" means a group -COOH.

The term "hydroxy" means an -OH group.

The term "amide" means a carbamoyl functional group

(-COXB2) or substituted carbamoyl (-CONHR, where B is typically C1-4 alkyl). The group of formula

-CONHR may also be represented herein by the formula -CQHH-, since the exact identity of the symbol R in the general formula -COHER is indifferent, as long as it does not prevent the formation of the remainder of the chelating agent and its attachment to the carrier moiety or interferes in any way with the objects of the present invention.

The term "imide" means a functional group of formula

-W

NH

-W

that is, the structure that faces the Imides (ie, compounds such as succinimide, phthalimide, etc.).

30SUU

The expression ^! The functional group is not essential for the complexing properties of said chelation agent. It is self-explanatory. Any functional group on the chelating agent which may be attached to the moiety of the carrier without destroying the ability of the chelating agent to form a complex with a radioactive isotope and considered herein not to be essential for the complexing properties.On the other hand, the derivation of a functional group that can lead to a structure containing a carrier and which is incapable of forming a complex with a radioactive iso is not within the scope of the present invention.

According to the present invention, the delayed delivery of a radioactive isotope to the brain in concentrations sufficient to. if your x-ray can be performed with much lower concentrations in the peripheral circulation and in other tissues. The present invention will of course permit to radiograph any other organs or glands in which sufficient radioactivity has accumulated. Thus, for example, the quaternary form (IV) that is retained in the brain is expected to be retained in the assays. See PCT patent mentioned above.

The novel radioisotope delivery system according to the present invention begins with the preparation of the novel vehicle-containing chelating precursors of Formula I. The preparation of these precursors will be planned with respect to the complexing portion envisaged and the portion of the vehicle to be combined, and in particular in relation to the nature of the chemical bond between them, e.g. depending on the bond being an ester or amide bond, as well as the presence or absence of other reactive functional groups (amino, mercapto, carboxyl, hydroxy) in both complexing or vehicle moieties. Typically, if these groups

recipes are present, will be found in the supplementary portion. In any case, when these groups are present and

to protect them, a step may be incorporated which introduces the appropriate protecting groups into a suitable station of the synthetic process. The protecting groups are well known in the art and comprise the butoxy, tert-carbonyl group for the amino groups, the N-methyleneacetamido group for the mercaptans and the N-hydroxy succinimidyl group for the carboxyl groups. The acyl or carbonate groups are especially used to protect gru

I-hydroxy of alcohols. When it is intended to use carbo groups

In the case of the protective groups, the phase of introducing the protecting groups will comprise the reaction of the alcohol with a halogen-carbonate of the general formula R0COCl or ROCOBr (resulting from the reaction of an alcohol

of the formula ROH with carbonyl chloride or carbonyl bromide, R being typically lower alkyl). For the acyl protecting groups, the alcoholic hydroxy group is reacted with an acyl halide of the general formula RC 1 or PBr, wherein R 2 is -COCH 3 ^or -COC (CH 2) 3. Other obvious schemes and reagents for

are understood in the art as are also suitable means for eliminating such protecting groups after having performed their function and ceasing to be necessary.

Re formation of precursors of formula I will bind at least one carboxyl group, hydroxy, primary or secondary amino, amido or imido, with a chelating agent, a ⁺ _7, form

of the hydrophilic ionic pyridinium salt of a dihydro pyridine ζ-pyridinium salt redox vehicle.

It will be understood that ⁺ J means any portion

non-toxic vehicle which comprises, contains or includes the

13

pyridine, whether or not a part of any larger basic nucleus, and whether substituted or unsubstituted, the only criterion adopted a chemical reduction capacity to ob having the corresponding dihidrpiridina shape / THC _7 _S penetration Z "DHCJ through the blood-brain barrier and oxidation of "THC-7" in vivo "to obtain again the portion of vehicle of

-Jsal pyridinium quatern river ^z / "HQ _7.

As mentioned above, the ionic pyridinium salt of the radioactive drug / carrier compound, of formula IV, resulting from in vivo oxidation of the dihydropyridine form of formula III, is prevented from effluxing from the brain while the X-ray radioisotope present in the quaternary form of the "retained" general formula IV allows observing the distribution of the localized radioactive isotope to diagnose pathological conditions, anomalies, etc. Subsequently, the union between the species

and the quaternary vehicle / "QCJ ⁺ is probably decomposed, which results in the easy elimination of the

"I"

of vehicle / QC7

The linkage between the chelate moiety and the quaternary vehicle may be a simple direct chemical bond, for example an amide bond or an ester bond, or any other similar bond or may be comprised of a linking group or function as illustrated in the examples or by the ethylenediamine group illustrated in the schemes 3 and 4. However, it is intended that the linkage is presented and is defined herein as such, inclusive of all such alternatives.

The possible decomposition of the quaternary compound of formula

general IV with easy elimination of the carrier portion

19

$ 00 30 $ 00

ι <* "* r? if" ^{η Γ} * ν ^ '^ ιι' * 'ΊΓί'

an enzymatic or chemical decomposition, e.g. by an amidase, irrespective of the type of cleavage "in the brain" which may result, whether enzymatic, metabolic or otherwise, clearly within the scope of this invention.

invention.

The many different portions of dihydropyridine redox vehicle ----- ^x pyridinium salt, shown below for uti

are simply examples of the many classes of vehicles covered by the present invention. Although the following list of

I vehicle classes do not claim to be exhaustive (and, in fact,

further classes of vehicles are described further in PCT patent application PCT / US33 / 00725), the following major classes of quaternary forms and corresponding dihydro forms are excellent examples of the portions contemplated herein.

(1) seldom binding to a chelating agent having at least one functional group, primary amine (-NH 3), amine. (-ΓΉ) or hydroxy (-OH), substituting a hydrogen atom of

) at least one of said functional groups by one of the following

groups represented by Z = C ⁷ :

(The)

li

R

O

II

R

O

(B)

0

II

30% to 30% ^;

(I.e.

(W)

R.

C1-4 alkylene-C1-4 alkyl,

(d)

Or

^{11 11} -CH ₂ CH ₂ -alkylene

R "

(and)

C £ R _n NH-alkylene-C / -, R3 ^y read ι Ρ

° ^Ε Ο (f)

□

wherein the alkyl group may be straight-chain or branched chain and contain 1 to 3 carbon atoms; R ₂ represents a radical identical to the corresponding portion of an amino-

natural acid; p represents 0, 1 or 2 with the proviso that when p represents 2, the alkylene groups can be the same or different and the R radicals represented by _Q are the same or different; represents a C1 -C6 alkyl group, halo-C1-4 alkyl, ^{or ara} 1Q. ^{A compound according to} claim 1, R 2 represents a C 1 -C 4 alkylene group; X represents a group of the formula -CONR 'R', in which R 'and R ", the same or different, each represent a hydrogen atom or a C1 -C4 alkyl group or X represents a -CH = of formula ROR where R ¹ "represents a hydrogen atom or an alkyl group C ^ Cr - ,; the groups bearing a carbonyl radical in the general formulas (a) and (c) and the substituent X in the general formula (b) may each be attached at the 2, 3 or 4 position of the pyridinium nucleus; the groups bearing a carbonyl radical in the general formulas (d) and (f) and the substituent represented by X in the general formula (e) may each be attached at the 2, 3 or 4 position of the quinolinic nucleus; and the groups bearing an alkaloyl radical in the general formulas (g) and (j) and the substituent X in the general formula (h) may each be attached at the 1,3 or 4 position of the isoquinoline nucleus;

(2) For binding to a chelating agent having at least one. carboxyl functional group, substituting a hydrogen atom of at least one of said carboxyl groups (-CONH) by one of the following groups represented by:

(a) When there are one or two carboxyl groups to be derived.

22

30S00; .3 ° « ^0θ

EÇÇUPO ⁵ .

(I.e.

/ \ LL

(C1-C4) -alkyl. ^u ι ^J P

And

O

RZ \

oV

AND.

(i)

By G-pyran-alkylene-G1 ->

^R

(II)

• ith COCH ^ C ^ alkylene-C ^ · - ¹ QZ E.

(iii)

0 0

It r II ·,

C-NH-alkylene-£ CJ- '^ -7> ¹ -.

(iv)

R - G-PEH-Gal · alkylene-QZ 3 ¹ II G ^G P ι

(V)

0

O

+ N

ο θ ^ + /

G -? Γ; There is. 1 qui 1 sno-cl ·, ZZ Ψ

R'1 II Γ ¹¹ t

• C0CH ^ C4-alkylene-NH ^ -Z-C4 _n

u | -1 p

B _o

(saw)

O

O

11 + - R -, - NH-alkylene-Cf-G4 _'r / 3 li, J t

G-7 ¹ ψ & 5

R,

1

(vii)

(viii)

. ; ¹ Λβαββ''OU

O

O

<x + N \ ZV /

0 0 0

J l _r II,

COCH3, -CH2 -NH-alkylene-C1 -C4 -alkyl.

Rn

(ix)

wherein the alkylene group may be straight chain or branched chain and contain 1 to 3 carbon atoms; R represents a radical identical to the corresponding portion of a natural sminoacid; p is 0,1 or 2, with the proviso that when p is z, the alkylene groups may be the same or different and E and _Q may be the same or different; Z 'represents a linear or branched C1 -C6 alkylene group, preferably an alkylene group

straight or branched chain; represents an oxygen atom or a group -H-; represents an alkyl group C ^ Cr - haloalkyl ?, G ^ -G ^ alkyl or aralkyl "io ^ '^ 3 ^re p" sit alkylene ^ C ^ -G; λ represents a group of the general formula -C0 ': R' R ', in which R' and E ', which may be the same or different, each represent a hydrogen atom or a C -C-C alquilo alkyl group; or X represents a group of formula -CH = NOR ^{1 '1,} in which ^R? "represents a hydrogen atom or a C1-4 alkyl group, the substituent represented by X in the general formula (ii), and the carbonyl radical containing groups in the general formulas (i) and (iii) may each The substituents represented by X in general formula (v) and the groups bearing a carbonyl group in the general formulas (iv) and (vi) may be bonded to the 2, 3 'or 4-positions of the pyridinium nucleus; , each one of them,

24

linked to position 2, 3 or 4 of the quinolinium nucleus; and the substituent represented by the symbol a in the general formula (viii) the groups bearing a carbonyl radical in the general formulas (vii) and (ix) may each be attached to the 1,3-position or the isoquinolinium nucleus;

(b) Alternatively, when only one carboxyl group may form derivatives;

(X)

The 4-G-β-NH-alkylene-G-θ-pNH-4-

(xii)

0 0

s

1

7

R

1

(xiii)

or

0

0

(xiv;

in which £ 30.00 '' 30.00 '

represents the skeleton of a sugar molecule

car; n _iv represents a positive integer equal to the total number of hydroxy groups in the sugar molecule of which the above-mentioned backbone is present; n represents a lower integer by one to the total number of hydroxy groups in the sugar molecule from which the above-mentioned skeleton is derived; each of the formula 1 in each of formulas (xii), (xiii) and (xiv) may independently represent a hydroxy or D 'group, D' being the remainder of a chelating agent containing a reactive carboxyl functional group , said moiety being characterized by the absence of a hydrogen atom of said carboxyl functional group in said chelating agent; and each R ^{1 '} in each of the formulas (x) and (xi) may independently represent a hydroxy group or a group of the general formula

II

0-4-C-alkylene-NH

C-alkylene-NH-4-rC

| θ E_

R

1

or D '

3 ' enr esent a

; and wherein s contains 1 to 3 carbon atoms;

radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkenylene groups may be the same or different and the radicals represented by the symbol may be independently or the same; 3 'has the meaning defined for the general formulas (zii), (zii) and ud.v); η

represents an alkanoyl group, halogen-1-yl

or araalkyl and the

. Jr

the grands indicated with carbonyl groups may be attached at the 2,5 or 4 position of the ringidium or orininium nucleus or at the 1, 3 or 4 position of the isoquinolinium nucleus; with the proviso that at least one of the each of the general formulas (r) and (ri) represents

A compound of general formula

i 1

alkyuylene

t

21

Ita I ^a

IY Λ ¹ ,, ·· ./Y · 'ibl · FSA':.! '' I '* ^1' ''

in which alkylene, R 1 and R 2, and the position of the groups which

have carbonyl radicals are as defined above; and with the proviso that when more than one of the radicals R 1 'in a given compound represents the said groups bearing carbonyl radicals, all those groups bearing carbonyl radicals in the said compound are identical;

(3) seldom binding to a chelating agent having at least one secondary amino functional group (-NH-) which forms part of an amide or an imide or at least one primary or secondary amino functional group having a low pH, a hydrogen atom of at least one of said functional groups by one of the following groups / ^"+ QC _7:

0 0

Ί Γ-. > U

G-jgrH-alkylene-οΑ-θΟΗ--,

R.

O

V

I,. i,

FL-C--C--C ^-alkyl _;

I - I

R.

(k)

(D

0 0

yl ii

i

R,

(m)

0

-J-OCH-,

wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R represents an identical radical and corresponding portion of a natural amino acid; p is 1, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals R may be the same or

many different; R2 represents a C1 -C6 alkyl, halo- (C1 -C4) alkyl, or aralkyl Γ, -Ο θ; E represents a hydrogen atom or a C1 -C4 alkyl, halo-C1-4 cycloalkyl, furyl, phenyl or phenyl group having as its substituent (s) one or more halogen atoms or lower alkyl, lower alkoxy lower alkoxycarbonyl, lower alkanoyloxy, halo-lower alkyl, mono-lower alkylcarbamoyl, di (lower alkylcarbamoyl), lower alkylthio, lower alkylsulfinyl or lower alkyl ) alkylsulfonyl, R ^ is an alkylene group of C, -C 5 X represents a group of formula -ΟΟΙ'ΪΕ'Ε ", in which R ¹ and R", which may be identical or different, repre Tam, or a group of the formula -CH = NOR '', in which R 1 '' represents a hydrogen atom or a C 1 -C 6 alkyl group, Cr, the groups bearing carbonyl radicals in the formulas (n) and (m) and the group represented by the symbol X in general formula I may be attached in the 2, 3 or the pyridinium nucleus; the groups bearing carbonyl radicals in the general formulas (m) and (p) and the group represented by the symbol X in the general formula (o) may each be attached at the 2, 3 or 4 position of the quinolinium nucleus; and the groups bearing carbonyl radicals in the general formulas (q) and (s) and the group represented by X in the general formula (r) may each

they are attached at position 1, 3 or 4 of the isoquinolinium nucleus.

Here and hereinafter the term "C 1 -C 4 -halogen" means a C 1 -C 4 -alkyl group having, as substituent (s), one or more halogen atoms. also

30500 130%

'ν -'? 'υΠΊί teTfWT

herein and throughout this specification, the alkyl radicals, and eluting the alkyl and alkylene moieties of other radicals, may be straight or branched chain unless specified

in another way.

The expression "E is an identical radical s corresponding portion

tooth of a natural amino acid "is explained by itself. This hand

for example, the symbol Εθ can represent a hydro volum

genus, such as glycine; a methyl group such as in alanine

as in valine; -CH, -CH (CH 2), as in leucine;

CH3,

t3

-CH2 -CH2 -CH2 -CH2 -CH3 -CH2 -CH2 -CH isoleucine; z 5

as in phenylalanine

as in tryptophan; -CH 2 OH as in serine; -CHOH-

as in threonine; - (CH2) _O- SCEL as in methionine; _The -C0N -CH £ L ·, d # ^7. dj ¹ cL έ.

in asparagine; As in glutamine;

-CH.

oOH as in tyrosine; -CE.SH as in cysteine:

-CH 2 COOH as in aspartic acid; and -CP-13-ECQOH as in glutamic acid. The term "natural aminoseido" used in the text does not cover dopa or L-DOPA. Preferred amino acids represented by _the symbol E comprise: glycine, alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine and glutamine.

The dihydro / THCy forms corresponding to the quaternary compounds mentioned above are as follows:

(1 ') For the group (1) above:

'30500 p 30 p0

SÍÍ 51

Αβ'όνΆ j.! Eur-lex.europa.eu eur-lex.europa.eu

¹¹ r ¹¹ 1

, .C4 -alkylene-NR-C-4 I ^{L G} P

I

Rn

N ^z 0

I rl ·

R 2 -C 1 -NH-alkylene-

(The·)

0 0

II II _Γ II ... .COCR.X + RH-alkylene-Cl ·

/ V ' ^τ i ¹

R.

i

Rn

R.

(B')

0

II

0

11

. ><.GF-RH-alkyl-C4- ₍

ZW ^τ i ^{T |}

-I R

(W)

R.

(d ¹ )

0 0

II II

A / V "" VR H-s-pentylene-C-

j 3: 12 · \ t _T ?

Cf-NH-alkylene-Gl '

³ II ^T I ^{Γ |}

^{0 K} o

(θ ')

(f)

oo

II _r II,

C1-4 alkylene-C1-4 alkylene,

, 2N

fc + T; H-alkyl ene-G-jR.

R.

(g *)

(g ")

22

or

-I

^x R -, - C '- {; cj-HH-alkylene,

Κ.

(H*)

3Ο θ0 30500

RT-Cf-HH-alkylene-Cl ·

³ ιι ^τ ι *

(h> 1)

-C0CH _Cf-HH-n-C4 alkylene or

OH - - - - - - -

ρττ

R.

R.

0

II

COCH2 C -f-I'TH-alkylene- ^C + p

(I.e.

W \

R.

(Γ)

(j ")

wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R _Q represents a radical identical to the corresponding portion of an amino acid in tural; p represents 0, 1 or 2 with the proviso that when p represents 2, the alkylene groups can be the same or different radicals and with R _Q may be the same or different; the dotted line in the general formula (a '), (b ¹ ) and (c') indicates the presence of a double bond at the 4- or 5-position of the dihydropyridine nucleus; the dotted line in the general formulas (d ¹ ), (e ¹ ) and (f) indicates the presence of a double bond at the 2 or 3 position of the dihydroquinoline nucleus; R3 is C1 -C6 alkyl, halo-C1 -C4 alkyl or C1 -C4 aralkyl; R 2 represents a C 1 -C 4 alkylene group; â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ a group of general formula

R ¹ is hydrogen or a C 1 -C 4 alkyl group; the groups bearing carbonyl radicals in the formulas (a ') and (c') and the group represented by the symbol X in the general formula (b ') may each be attached to the 2, 3 ^or dihydrpyridinium nucleus the groups bearing carbonyl radicals in the general formulas (d ') and (f ¹ ) and the group represented by X in the general formula (e') may each be attached to the 2, 3 or 4-positions of the dihydroquinoline nucleus ; and the groups bearing carbonyl radicals in the formulas (g ¹ ) and (j ¹ ) the group represented by the symbol X in the general formula (h ¹ ) may each be attached to the 1, 3 or 4 position of the dihydroisoquinoline;

(2 ') Rare the group (2) (a) above:

0 0 II r H,

and A? C? -NH-alkylene-C?

II ^E n

\ / ⁰

(D

Sr 0

¹ r L

R.-C-p-NH-alkylene-C1-

³ II | ^[J

0

(ii ')

oo

il II

0

II

C ¹ -C 4 -alkylene-C ¹ -C 6 -alkyl, -

.0-f RH-alkylene-Q-Z

AZ ^L I ^J P

(I.e.

Rn

(iv)

or

II

R-CF-NH-alkylene-O- ^ ¹ CXT-3 - yl C ^[J P

(ν ')

'3i

2

UU \

(vii ¹ )

(I.e.

Î'30.00 Î »30 C

0 0

^{11 11} 1 ¹¹ I,

CO-CH 2 -NH-C 1 -C 4 -alkylene,

R.

¹¹ Γ

C-NH-alkylene-

\ / \ lZ \ r II η

 € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡

(viii ¹ )

/ i.

λΛ

W \

β) - COCH2-C (NH) -alkylene-

rh

RT-CJ-NK-C4-alkylene = -uZ ¹

³ ir i

^{0 B} o

(viii ")

(iX ')

or

.

0 or 0

C0CH KH ₂ £ C-C-alquilem Jg-O-2 '-, R

(ix ")

wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R represents a

O

radical identical to the corresponding portion of a natural arachinoid; p represents 0, 1 or 2, with the proviso that when the number 2 is given, the alkylene lumps may be the same or different and the radicals represented by h may be either individual or different; the dotted line

(i '), (ii') and (iii ') indicates the presence of a double bond in any of 4 or 5 of the nomenclature, dihydronyridine group; the row set in the formulas (iv ^f 5,

(ν ') and (vi') indicates the presence of a double bond in any of the 2 or 3 positions of the dihydroquinoline nucleus; 3 'represents a linear or branched chain alkylene group, preferably a straight chain Ο-CL-alkylene group ??? or branched; Q represents an atom of the parent or a group of -GI-; represents a 0 -, - Ίγ, halogenoalkyl or aralkyl group Ιγ-Ο'ηθ; R 2 represents a group at the

is a group of the formula ^:

in which R 1 and R ² , which may be the same or different, each represent a hydrogen atom or a C 1-6 alkyl group, or X represents a group of the general formula -SO 2 CN. which "f" represents a hydrogen atom or a

the group represented by the symbol Σ in the general formula U '') and the group bearing a carbonyl radical in the general formulas (i) and (iii ') may each be attached to the 2, 3 or 4 position of the dihydropyridine nucleus; the substituent represented by M in formula (v *) and gruro having a carbonyl radical in the general formulas (iv ') and (vi ¹⁾ may each ura them being bonded at position 2, 3 or 4 core dihydroquinoline; and the substituent represents 30%

Tado by X in formula (viii ') and groups that carry a carbonyl radical in the general formulas ⁽¹ vii) and (ix ¹⁾ can each be linked to position 1, 3 or 4 dihidroisoquinolínico core;

(3 ') To the group (2) (b) above:

(Xi *)

u

II _r h 1 '

C j-C j-C j-C j-C ^-C ^-C ^-C ^-C ^-

O _n V

(xii ')

«II

C1-4 alkyl-NH-

R,

(xiii ¹ )

'/'

_{N (} v)

Γ - t \

-H-C1-4 alkylene-NH-

O

(xiv *)

(A) _n v

OR

or

or

(I.e.

wherein the alkyl group may be straight or branched chain and contain 1 to 3 carbon atoms; R _q represents a radical identical to the corresponding portion of a natural amino acid; p represents 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals R ₂ can be the same or different; the dotted line in the general formula (xii ') indicates the presence of a double bond at any of the 5-positions of the dihydropyridine nucleus; the dotted line in the general formula (xiii ') indicates the presence of a double bond at any of the 2 or 3 positions of the

* * *

dihydroquinoline nucleus; · * Represents the skeleton of

* /

a sugar molecule; n represents a positive integer equal to the total number of hydroxy groups in the sugar molecule from which the above-mentioned skeleton is derived; n represents a positive integer lower than one to the total number of hydroxy groups in the sugar molecule from which the above-mentioned skeleton is derived; each A in each of formulas (xii '), (xiv ¹ ) and (xiv ") may independently represent a hydroxy or L' group, D 'being the remainder of a chelating agent a reactive carboxyl functional group and said moiety being

130 øCi ^: 130 Å

iCUDOS

carboxyl in said chelating agent; and each R ^ ..- ur symbol in each of formulas (x) and (xi ¹⁾ can independently represent a hydroxy group or a group of formula

0 0

r "· ... O

-O-alkylene-Ό

R

1

or D ',

wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; Εθ represents a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals may be the same or different; the dotted line has

as defined for formulas ⁽¹ xii) and (xiii '), D' is as defined for formula (xii '), ⁽¹ xiii), (xiv') and (xiv ^11); R ^ is a C--C alquilo alkyl group; aralkyl or Cj-mentioned L and carbonyl groups may be attached at the 2, 3 or 4 of the pyridinium or quinolinium nucleus or unless it is specified otherwise in position 1, 3, 4 ^naked isoquinoline nucleus; with the. provided that at least one of the symbols in each of formulas (x ¹⁾ (x ') is a group of formula,

0

li

4 '. 1 .

C-alkylene-dH-f-G

(I.e.

0 0

r ". ¹¹

A. 1 qui 1 and no - 3 n C

K

R,

or

in which alkylene, R _Q , p, R p the dotted lines and the position of the groups bearing carbonyl radicals have the signi

40

3rd oo

'λ ¹ ·.' · '

i love you

L. · E5Cttâ »¢ 8

defined above; and with the proviso that when more than one of the radicals R 1 in a given compound represents the groups bearing the abovementioned carbonyl radicals, all such groups bearing carbonyl radicals in the said compound are the same,

(4 ') For the group (3) above:

C-fNH-C1-4 alkylene-OCH

\ _{T. T} Z

(k ¹ )

R β "C-E * NH-alkylene-C ffp-OCR-, E

O

(T)

0 0 0

II ur II -i

. C6 -C10 alkylene, -C (= O)

R.

(I.e.

^B i

¹¹ Γ 0

. . X-O-alkylene-C-kr-OCi

a / kri

(m *)

(n ¹ )

3 ' ,2:

'1

 € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ

(θ ')

0 0

ll II

HpO-cMH-alkylene-

(P')

(I.e.

II _Γ II -,

C1-4 alkyl-C1-4 alkyl,

S / K + V R.

R (q ')

ΓΑ-X 2 N

THERE

; 30 $ 0Ο '30 $ 0Q

R

R--G-h-H-alkyl-Cg-C (-CH₂ (R ')

THE.

31

W \

(i.e.

II

C1-4alkyl-NR-C4-

J || * - I • Jp

0 R

(r ")

.

C 1 -C 10 -alkyl-O-CHO

The tj

R.

(s*)

1

(s")

wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R represents a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals represented by the symbol θ may be the same or different;  € ƒâ € ƒâ € ƒR2 represents a hydrogen atom or a C1 -C6 alkyl, C1 -C6 cycloalkyl, halogeno-C1 -C6 alkyl, furyl, phenyl or phenyl group having as its substituent (s) one or more halogen atoms or lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyl, lower alkoxy, halo-lower alkyl, mono-lower alkylcarbamoyl, di-lower alkylcarbamoyl, alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; the dotted line in the general formulas (k ¹ ), (1 ') and (m ¹ ) indicates the presence of a double bond at any of the 4 or 5 positions of the dihydropyridine nucleus; The. dotted line n s

formulas (n ')>(o') and (p ¹⁾ indicates the presence of a double bond in position 2 or 3 of the dihidroquinolínico core;

λ represents a group of -COORR'R ", wherein R 'and R", which may be the same or different,

a hydrogen atom or an alkyl group or X represents

R s represents a hydrogen atom or a C ^-C alquilo alkyl group; the

groups bearing carbonyl radicals in the formulas (k ') and (m') and the group represented by X in formula

(1 ') may each be attached at the 2, 3 or 4 position of the dihydropyridine nucleus; the groups bearing carbonyl radicals in the general formulas (n ¹ ) and (p ') and the group represented by X in the general formula ( ¹ ) may each be attached at the 2, 3 or 4-positions of the dihydroquinoline ring ; and the groups bearing carboxyl radicals in the general formulas (q ¹ ) and (s ¹ ) and the group X represented by the general formula (r ¹ ) may each be attached at the 1, 3 or 4-position of the dihydroisoquine nucleus

nolínico.

The presently preferred dihydropyridine-3-pyridinium redox vehicle moieties according to the present invention are those in which p is zero or 1, with zero advantage; the alkylene group, when present (i.e., p = 1 or 2), is the methylene group (-CEL · -); R 2 when present (ie, p = 1 or 2) represents a hydrogen atom or a methyl group,

X represents a group, when present,

represents a -CONH2 group;

(a) and (c) and the group X represented by the general formula (b) position 3; the groups bearing the carbonyl radicals indicated in the general formulas (d) and (f), and the group represented by the symbol X in the general formula (e) are attached at the 3-position; the groups bearing carbonyl radicals indicated in general formulas (g) and (j), and the group represented by

X it onto _the eneral formula (h) is attached at position 4; Z ', when present, represents a straight or branched chain alkylene group having 2 or 3 carbon atoms; Q, when present, is -NH-; O

(iii), (iv) and (vi) are attached at the 3-position, the group represented by the symbol X in the formulas (ii) and (v) and the groups bearing carbonyl radicals indicated in general formulas (i) represented by the symbol X in the general formula (viii) and the groups bearing carbonyl radicals indicated in general formulas (vii) and (ix), are attached at the 4-position; (xii), (xiii) and (xiv), are in the 3-position of the pyridinium or quinolinium nucleus and the 4-position of the isoquinolinium nucleus; all symbols E '^ in formulas (x) and (xi> represent hydroxy groups, except a symbol E ¹ ^, in each formula, which must represent a vehicle tion, all the symbols A, in the general formulas ( xii),

X ~ *

(xiii) and (xiv), represent hydroxy groups; represents the skeleton of a glucose molecule; E in general formulas (X), (1) and (m), represents a hydrogen atom or a methyl or trichloromethyl group; and groups that

include the carbonyl radicals indicated in the general formulas

(m) to (ε), are in the 3-position of the pyridinium or quinolyl nucleus and the 4-position of the isoquinolinium nucleus; and the corresponding dihydro moieties.

Particularly preferred moieties of the dihydropyridine pyridinium salt redox carrier are the compounds qua

(a), (b), (d), (e), (g) and (h); those of Group (2), formulas (i), (ii), (iv), (v), (vii), (viii), (x) and (xii); and those of the group (3), the general formulas (k), (1), (n), (o), (q) and (r); and the corresponding dihydro forms, more especially when they fit the preferred structural variables identified in the previous paragraph.

The following synthetic schemes illustrate various routes for the preparation of vehicle-containing chelating agent precursors of Formula I to provide the corresponding vehicle-containing chelating agents of Formula II and the corresponding vehicle-containing radioactive drugs of Formula ₆ III. Also indicated are the corresponding "retained" quaternary compounds of formula IV formed by

) "in vivo" oxidation of the chelates of general formula III, the

Quaternary compounds of general formula IV

* localized primers whose radioactive isotope content is radiographed by means of radiation detection devices.

EsqEsquema 1

CH₂-CHCOOH

I

NH | RH | C | C = i | CH, - _; 1 * CH, | ' W W

k

f I Η H

HO- (CHz-Jp-I

--->

DCC

(a chelating agent described in Fritzberg bears US R ²

4-ΛΨ + .69Ο)

1

CH ₉ -COOH

0C1,

HUH

0 = C

NH

i

C = 0

CH

çh ₂

CH ₂ -CHHC (CH ₂ ) ₂ -I

HH HH

I i

O = C G-0

CHÃ GEL ·

i 2 I z

COREL,

Yes = cc = o

ll II

1

Scheme 2

H, NO.

E, .NCR, CHCOOH

(I.e.

tt

i.e.

or ο ο

I

0-0

I

's "CO,

3

30 $ 00 '30 $ 00

• VRIMTA! j TRI8TA ESCUDOS ESCITOOS

^ Q * N- (GH _{2) 2} -0H

H ₂ KCH ₂ CHC (CH ₂ ) ₂ -N ⁺ q

NH,

COKHn

(I.e.

I

c = o

I

CH, CH,

| I <

Î'HCOO (CBO),

CH, -CHCOO (t H,)

ÍJOEH.

; ONH,

Reduction eg

with Na, S, O «ϊ

dalinc

half a.

(1) NaHCO.

3

(2) ClCE, COCl

CH, -CHCQQ (C NH I NH I 1 ^: C 1 1 0 = 0 1 CH, 12 CH, ^1d Cl Cl

in ro

+ 1

0 = o

ι

NH NH

C = O

I

CH, CH,

ι £ ι έ.

.coih ₂

-CHC0u CH (CH) ,, ·

IRI ά c.

CON

Έ2

1½

Sc-99m pertechnetate and

reduction agent

ι

H

s

i

H

reduction

Esquems 2 (continued)

C00 _(g CH) ^ - NO

COUBE

is.

Form 'retained in the brain'

] squema3

30 $ 00 30S0Q

<·.>

^Τ * ^1ΝΤ Λ í Schools

TR4MTA CSCUO0S ¹

, NfL

FIG.

13 ίέϊ.

0 t-EOC

ZZ

zoe

0

(I.e.

DCC

15

16

L

16

IZ

Scheme 3 (Continued)

H 0 x 1 I

14 + 17

t-BOC

i ^z * ^X If ' ^zA \ / ^Z

SH

18

18

HCl

z- ^c 0 I

CHSli

1J

99.

respectively.

TcO

H 0 I II

n-c

H

l

ΊΊComplex cie ^^ TeO with reduction of the pyridinium nucleus

20

oxidation in vivo

Quaternary form of radiopharmaceutical "held in" Brain ₌

21

50

Scheme 4

hi

H

CH,

23

24

24 ♦ K ₂ N

2J ♦ 99

tco

*** 2 ^ 2®4

OH "

Complex with reduction of the pyridinium nucleus

.27

I oxidation ^V / in vivo "

Quaternary form of active coronary artery "retained in the brain"

28

51

Scheme 5

N ₂ NCH ₂ CHC00H

RH,

CH3 OH

->

MCI

, COMH,

çh ₂ - _Ç hch ₂ ococh ₂ - «Y)

NH NK i ·

β-c ce

aa

CH, CH,

R

COKH,

H ₂ HCH ₂ CHC 100 C ₂ H _s

nh ₂

30

reduction (eg ccm

LiAlHj U * 4

H ₂ HCH ₂ CKCH ₂ OH

nh ₂

31

CH; I ²

NH

I

0 <

I

CH; I ^Z Cl

• CHC00C ₂ H ₅

NH

I

C-0

I

CH;

I ^L Cl

r-

CK ₂ - CHCH ₂ 0C0CH ₂ Br HH HR

0 »è Ç-0

çh ₂ çh ₂

ss • ι

36

35

I

(I.e.

ι

0 = C

CIX

I

O

w

I

H

3.6

Scheme 5 (cont.

COEHrέ.

reduction, eg with

in the middle of nowhere

linen

ii [ιι · Γΐιιηηιιιι-r.] rri »* - in'iiinniffn-inmuTwnir rf

0 = C = = 0

CEL · CH ₅

ι ZI

ciaa ^ k /

I

H

37

form, "retained in" brain.

51

Scheme. 6

Η 'ΧΗ, ύΗϋΟΟύ-Η, ά 2 5

ΝΗ,

CH3 -CH2 -CH3

30

(1) KaECCL

(2) GLGILGOCl

Q = C CO

II

54

HHg-KKCONH

CClj

Ihoh

Scheme 6 (continued)

MH

oc

CH,

MH

I

C-0

s

i

N

43

nicotinic acid

occ

Thirty and C.SCUCOS

CC1 ₃ CH t-K ^ - ÇHCONHêHOÇ ÓQy MH-0 HH \ -1

I

OC

ÇK ₂

s

i

H

C-0

CH ₂

s

THE

44

CHI

CC1

i

CH, -CHCOHCHCHOC

I

NH

i

C-0

CH, CH,

I - | *

ss

I

H

MH

i

OC

4S

reduction, eg ccm Na ₂ SO 4 in alkaline medium

I ^C '_ ³ / f ~ \ ³

CHCOKHCHO-C H H O

C-0

5 'z

s

*

H

46

oxidation "in vivo"

COHKCHO?

medium "retained" in the ^CCL cêreibro

<8

Scheme. 7

-CHCQOCH. id 5

nk ₂

EOOgGH-CHGOOH1NH. NH.

zd

CH _and OH

j 5

HGl

EXAMPLE 5

Ih ₂

; 2,3-Glymino-succinic acid)

50

(1) C H ₂ COC 1

* u) <0

0

II

CSNa

z

^x G

GE1 z - CM 1 EH 1 = c NH 1 C-0 (1) NH3 CH. IS (2) THE 1 c kJ 1KJ V 1111

l

H

i

H

GK _c OOCCH-CI-ICOOC.H _r M 5 I i 25

. X

IM *

0-CC = 0

II

CH. EC.

I d, J

51

53

HCHO

GEL · OH

id

\ z

CH-CH

II

HUH

I

QC

i

HE

£>

I

H

i

C = 0

i

CH ,.

1

s

I

H

nicotinic acid

DEC

X.

\ CH - 1 Ί G Z-CH 1 NH I 1 '= C | G = 0 CH. 1 ^to | CH. I W W u * 1 I H I TT

54

55

Ic-> 9n pertechnetate and reducing agent

and g

alkaline medium

in

0

li

5t

reduction,

K a, &. 0 'za * +

alkali

eg with in medium

çh ₂

CH- I xC -CH KH 1 KH | 1 V C-0 | | CH _O OH, - 1 ^d 1 s s

i

H

i

H

5.6

• N

CH-

Scheme 8

30 $ 00 30 $ 00

K ^ NOG

+ \

TZ QY-COOH / Q N- (CH ₂ ) ₂ -OH

gONH.

(3,4-diaminobenzoic acid)

53

60

(1)

(2) C ₁ H ₂ COC ₁

₂ L- / o

HSCH

-GOO (CH3) ₉

is. W.

FHCCHoSH

II ^d

0

I

Εεquema 8 (cont.)

0

^; slh ₂ c: h- (q

C ₂ -C ₂ (CB ₂ ) ₂ -N q '

MHCH3 CH2 SH

II

Q

G0í'ih _o

63

reduction eg with

(Ii) alkaline earth

, COREL ·,

d.

Tc-99m Pertechnetate

and reducing agent eg ^C 20 ^S 20 ⁱⁿ an alkaline medium

HSCH ₂ CRH- (q) -000 (0)

RHCGH _The SH Il έ

0

64

UsTcOi / reduction agent H0

II

.Tc '

c // \ P ~~~ 7 -BS

CP- _x / - * 0

C00 (GH ,.) _a -N d. d ¹

CGIH,

Oxyacylation

0

COPE,

COO (CH 2) _O -N

d. d

Form 'retained in the brain'

66

65

59

Scheme 9

30 $ SOIOO *

^ 2,

H ₃ C

HjC

Eur-lex.europa.eu eur-lex.europa.eu

CHINOHJCCOOCjKj

69

68 + 70 pyridine

1,

HCl /

til

CH CH

II

ϋΖ> Λ ' ³

njU 0 »d Vrlj

71

NK:

68

CI "H ₃ N ⁺ CH ₂ CHC ₁₀₀ C ₂ H ₅

NH2 *

70

ch ₂ nh ₂

NH NH

K, C ·

: h ₂ ch ₂

C? ^H ?

H SH

70

I, CH,

HCl

dihydrochloride of 74

60

I

61

Scheme 10

7

IR (CHCl 3)

Ν «2

30

CHCNOHJCCOOCjHj

reduction, eg with LiAlH2 +

--- »

reduction (eg with LiAlH 3)

HCHnOH

nh ₂

31

81

HCl

ether

^ ck ₂ oh

(1 H-HCl NH-

II

H ₃ C <* ^ 2 C ^H 2 CH ₃

c ^c

^H 3 ^C SH SH ^CH 3

81st

62

'30 $ 0Q

Ri

HH

81

Scheme 10 (continued)

ch ₂ oh

HH

Ih

, "2CH ₃

CH,

H, C _X ^'K 3 ^C 2 ^H SH

C? 2, CH?

XcH.

SH ^CH 3

83

Tc-99m pertechnetate reducing agent e.g. Na₂SO ^, in alkaline medium

NaTcOy reduction agent

/ '3

HjC

HjC '

oxidation 1 - " ^{iri v ive} "

"retained" form in the brain

reduction, eg with Na ₂ S _{2 4}

in alkaline medium

, CH,

(i.e.

Ih ₂ 0¾

CH3

'XHj H SH * W

Scheme 11

30 $ OO

^{ΐ Ι} * 1 »* ^{Α.Φ Ι}

68

(I.e.

Μ

(I.e.

90

οτο

91

64

Scheme 11 (continued)

Oxidation "in vivo"

ψ- 94

Quaternary form of the drug

radioactive retained in the brain

65

Scheme 12

H 2 NCH ₂ CHC00C ₂ H5

NK2

30

(1) No ^ COj

(2)

ch ₂ - chcooc ₂ h ₅

NH NH

II

O-C-O

ii

CH ₂ -CHCNH ₂ MH ₃

NH NH

I, / 0-C C-0 ^x

l I

CH, CKn

4h 7

42

liaih ₄

(I.e.

ch ₂ - chcooc ₂ h ₅ NH | NH I 0 < C-0 1 1 ch ₂ CH _? I * s s 1 1 0-C C-0

41

CK ^ ₂ -CHCK

NH NH

0-C 4-0 ond / or

CH, OR

II

SH SH

ch ₂ -ch ₂ nh ₂

NH NH

¹H ₂ CH 2

CH ₂ CH?

4H

97

98

66

Scheme 12. (continued)

97

100

CK2KH

i

0 <

reduction, eg with Na ₂ S ₂ O ₄ in alkaline medium

i

C-fl

i

ch ₂

SK

101

J oxidation I ¹¹ in vivo "

"retained" form in the brain

67

Scheme 12 (continued)

30 ° C 30 ° C.

Μ ^Γ ;; Γ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ^-

CH-

NH ItH »

CH,

I * "

I » ²

(r

SH

16

ch ₂ - hch ₂ nhc- / q \

NH NH '-'

"2" 2

.

I

SH

I

SH

98

Tc-99m pertechnetate and reducing agent, eg 2820 ° C, in alkaline medium

NaTcO 3 / reduction agent

104

Jí

CH, I

XH,

_S U- _S

107

ch ₂ nhc

oxidation "in vivo"

CH, I * NH çh ₂

₇ I ^I SH CH

-hhh ₂ nhi

NH I

çh ₂

ch ₇ I ^Z SH

105

reduction, eg with ^Na 2 ^S 2 4

in alkaline medium

0

C H ₂ -CH ₂ NH ₂ - σ Λ

NH ₂

SH: SH

106

NH

CH, ^z ,

"retained" form in the brain

68

Scheme 13

3θ σσ} 3osoo 1

IR

N1,

31

butyl chloroformate tert.

t-BOC-NHCH ₂ CHCH20H

NH-t-BOC

109

(1) butyl tert-lithium

(2) ICH3 OH

CH ₂ - CHC ^ OO ^ CH ^ NH H NH ₂

111

(1)

(2) CH2 Cl2

H*

t-BOC-NHCH ₂ CHCH ₂ OCH ₂ CH ₂ OH

NH-t-BOC

110

ç ^ - jhch ₂ och ₂ ck ₂ oh

NH

0-C

ch ₂

Cl

NH

I

C-0

4

Cl

is not

NH

1

oc

I

CH · 1 '

CH ₂ -CHCH ₂ OCH ₂ CH ₂ OH

NH

1

Ch

çh ₂

112

113

ch ₂ I

NH

I

OC

I

CH

SH

chch ₂ och ₂ ch ₂ oh

NH

1

C-0

CH ₂

/

SH

114

69

Scheme 13 (continued)

3rd a

116

I "

reduction, eg with Na ₂ S ₂ O ₂ in alkaline medium

0 \.

NaTcOy '

netting agent

CK _? I ^z NH i

• CH,

OC

i

CH ₂ 0CH ₂ CH ₂₀ C

CH; I * SH

0 ^

-CHH ₂ OCH ₂ CH ₂ OC-C Λ

NH '-'

I

C-0

I

R SH ^z CHâ,ƒ

117

118

CH ₂ 0CH ₂ CH ₂ 0

X '

119

"retained" form in the brain

70

Scheme 14

ooh

HCl

(3,4-diaminobenzoic acid)

59

.

120

CDNoHCO2

(2) ClC2CO3

9

CIC ^ CH

NH4 Cl

121

NaBH4 / acetic acid

v

KSCK2CH2NH

0 / -¾¾

H

RHÕÃOt,

124

71

Scheme 14 (continued)

12 «16 1? 5

»·

(I.e.

oxidation "in vivo"

W.

'27

"retained" form in the brain

72

Scheme 15

h ₂ k-çQV-cooh ² 59

CICIOU

tetrabutylammonium borohydride

<Â, "C H â,

B

fHH

C1CH2CNH- / QS-CH2 ¹

OH

NHCCHnSH

5 ²

135

0

73

Scheme 15, (continued)

HSCH

CH?

m / z 2, δ ²

reduction, eg with Na 2 O 4 in an alkaline medium

Tc-99m pertechnetate and reducing agent, eg Na 2 S-Ch, in alkaline medium

CNH ESC ^ _ ^ - CH / Hf _{1 7} ^ SH HHjC

/

NaTcO 3 / reduction agent

0

"retained" form in the brain

Scheme 16

30S0Q

(1) methyl lithium

δ </ "3 * nhcch ₂ sh _w6

1 '7

75

Scheme 16 (continued)

30 $ 00

HSC2 ch ₂ och ₂ ch ₂ oc

107

, "/ *

1'

reduction, eg with? 2820 in alkaline medium

Tc-99m pertechnetate and reducing agent, eg 2820 ° C, in alkaline May

NaTcO,

⁰ 0 n ^xh

hsc ^ h ^ ci ^ och ^ oczf

agent of

f-Crt

108

, CH,

109

CK20CH ₂ CH ₂ 0C-M Λ

Oxidation "in vivo"

0

"retained" form in the brain

76

Scheme 17

dibutyl dicarbonate tert.

CN

KH2

H, N

CH2 CH2 H0 -CO

NH,

155

157

77

HSCH

CH ₂ NH

1"

Scheme 17 (.continuation)

£ Hj reduction, eg

NR * r \ rc \ Nta C Π

camNa ₂ S ₂ O ₄

in the al-) -

calino v nhçch ₂ sh

158

Tc-99m pertechnetate and reducing agent, eg Na ₂ S ₂ O ₄ , in alkaline medium

_n ^H 3

ch ₂ nh

NaToO./ reduction agent

"retained" form in the brain

78

Scheme 18

cnch ₂ cooh +

DCC

CHCH, COO-N

Ι

N

167

r

NH I

CH, ^z, -C

^H 3 ^cX V

H ₃ c.

NH

I

CH

2 / CH,

H, C

♦ 167 ³

• CH,

NH i

CH, ^h 3 ^{c /} S

ncoch ₂ cn

"2 C- ₃

CH,

88

168

LlAlHn

H, C

h ₃ c

NH NCH ₂ CH ₂ CH ₂ NH ₂

The C ^H ₃ CH 2

SH

SH

CH,

169

169

169

CH,

17

171

79

Scheme 18 (.continuation)

Complex with technetium, redox system in reduced form

173

oxidation "in vivo"

Quaternary form of radioactive drug "retained in the brain"

174

80

Scheme 19

CrH ₃ N ⁺ CH ₂ CHCOC ₂ H ₅

HH ₃ ⁺ C1 ·

70

C1COCH C1 ₂

C00C ₂ H ₅

NH

i

O

I

CH ^z Cl I

NH

I

CO

I

CH ^z Cl I

/ 40

<Q>

Cost

z cooc ₂ h ₅ NH NH 0 = C CO CH, ch ₂ SH SH

NoOH

NH

I

0 = C

ch ₂

s

i

0 = C

175

^ C00C ₂ H ₅

NH

I

CO I

çh ₂

s

i

c = o

<41

CONH,

ich ₂ ch ₂ oh

ÊT · ^Σ Νch ₂ ch ₂ oh

176

175 + 176

ONHn

i

CH, CH ₂ COO i ^z

NH

I

o = c

CH,

i

SH

NH

I

CO

i

CH,

i

SH

3

81

Scheme 19, (continued)

CONH _c

NH

i

0 = C

CH ₂ SH i ^z

NH

i

C = 0

i

CH, ^{z z}

reduction, eg oom Νά ₂ δ ₂ Ο ^, in alkaline medium

xcontinues as in the scheme

6

COOH

5 '

Scheme 20

COOH

♦ cicoch ₂ ci ->

NH | NH 1 co co ch ₂ çh ₂ Cl Cl

Ejaculars

NH CO NH 1 co ch ₂ 1 ^c ch ₂ s s co co (q) and

coconuts

II

CH ₂ CH, ι i

Sf SH

63

I is CH ₂ CH, i ^z l SS

I '

CO CO ₂ CH ₂ CH ι ^{ι ί} SS i ^z CO CO

continues with Scheme 8

83

Scheme 21

TR4HT »

SHIELDS

coconuts

yl CH, CHn ι ^z ISS

II

COCONUTS

nh ₂ ch ₂ ch ₂ oh

conhch ₂ ch ₂ oh

180

DME

179

çh ₂ çh ₂

ss

hi

COCONUTS

CONK,

co

I

ch ₂

I * s

BrCH ₂ CH ₂ NH ₃ Br *

co

çh ₂

s

CONH,

ΒΓ ^'i

CH ₂ CH ₂ NH ₃ Br '

183

181

co

I

co

.79 + 183

çh ₂ çh ₂

ss

II

coconuts

iè>

182

84

form "retained in the brain"

85

Scheme 22

178

Ç ^h 2 ÇH ₂

COOH

NH,

NH NH2

COCONUTS

çh ₂ çh ₂

SH SH

188

CH, CH ^?

SH

ch ₂ ch ₂

Jah

63

189

continues with Scheme 8

66

7Ji ♦ 191-> 76

continues as in Scheme 9

76

79

87

HjC.

h ₃ cNH

i

CH _?

i

W

i

SH

ch ₂ nh ₂

NH

i

f ^H> _CH3 ^CH3 SH

74

Scheme 24

ch ₃ -c-ch ₃

/ \

u_r

n ₃ U

-N

I

CHn I * Λ,

\ lz

79

H ₃ C _x

H, C '

W·""

h ₂ nh ₂

I Ç ^H 2 s ^ _c

h ₃ c 'h ₃ h ₃ c' XH ₃

192

17 0 191

ch ₃

'CH,

ch ₂ nh:

r

N "

I

CH, I ^Z

THE'

/ ^CH 3

IX,

CH,

H ₃ CH ₃ H ₃ C CH ₃

193

continues as in Scheme 9

88

Scheme 25

NH 1 NH co CO | çh ₂ X s 1 s co co

SOCl ·

II co co

(o) (g)

B

çh ₂ çh ₂

ss

ii

coconuts

(8) (°)

CH ₂ CH ₂ i * i

SH SH

Continues as in [Scheme 14

89

Scheme 26

X ~ \ ₂ 0 .C0NH

(Qj * H0-C-CH ₂ Br -> (Ο} ^Br

io CO

197

199

90

Scheme 26, (continued)

91

Scheme 27

HjC CHj

192

CH, NH

12ΠΠ2

Ν'-

CH ₂

(CH)

CH

ch ₃

0

BrCH ₂ CCl ->

h ₃ c ch ₃

h ₃ c ch ₃

203

With

. X.

92

Scheme 28

ky w

HiC NH,

³ \ / ² C

(X) H

CH ₃ Ll

HiC HH,

³ \ / ²

W

H ₃ C ^Z \ 0CH3

hsch ₂ ch ₂ sh

BF,

<3 / ^H 2

I

HjC C

204

CH-OAc

CHO CHO

205

H, C

^{3 x} c ^Z

CHOAc

W?

CHCH II N

204

CH,

h ₃ c

if whether

1

'cJ I-s ²

^N \ / ^{CH3 | Xs} CH

CH,

ch ₃

205

(1) nqbh ₄

(2) H ⁺

ch ₂ ch ₂ nh ₂

7-

/ X ^ COON

OA

(I.e.

I

CH,

£ ₂ CH ₂ 0NHCH

CH, -N

^CH3

c c - CH, / O ^z X ³

CH,

C-C-CH,

H, C CH

2c9

Scheme 28 (continued).

i

CH,

C0NHCH ₂ CH ₂

CHn-NH

ch ₂ -nh

.Cs

HJC _x ^ CH

CH,

209

h ₃ c

c-ch-ch.

CH,

reduced

213

H, C CH ₃ ³ / ^h ch ₂ nhccch ₃

CH NHCCCH ² / \ H ₃ c CH ³ ₃

nh ₂ oh

oxidation

The quaternary form of radioactive drug "retained in the brain"

212

214

94

Scheme. 29

Ο Ο ιι ιι

Cl-CC-Cl

nh ₂ ch ₂ ch ₂ nh ₂

or

cNH

CH,

lh ₂

NH,

O

•and

nh

çh ₂

çh ₂

NH,

215 (from a mixture of ~ products)

(I.e.

ι

CH,

η ₂ ν

NH. NH- Γ NH CH r 217 < NH

LIAlHi

h ₂ n

NH-

reduction, eg with

Tc-99m pertechnetate and reducing agent, eg Na2S2O4, in

^In 2 ^S 2 ° 4 '.

216

H, N

V alkaline

Complex with technetium, redox system in reduced form

219

NaTcO 3 / reduction agent

C-NH

B

NH.

NH-

N

I

CH

218

oxidation

"in vivo"

(I.e.

Quaternary form of radioactive drug "retained in the brain"

220

22

Thus, Scheme 1 above illustrates

30 $ 00 '' 30500

»ΛΙ!> ¹ '"<11

· -> til 599 »5 s TRLMTA Ί? TRiMTA and E5CUO08

a route of synthesis

typical for compounds in which the bond between the vehicle and chelate moieties is through a carboxyl group in the chelating agent. In the first stage, the reactant alcohol may be generally represented skin-H0-2' formula I, in which Z ¹ represents a C₁ to C₆ alkylene group, straight chain or branched; in the second step, the indicated reagent, nicotinamide, can be readily substituted by picolinamide, isonicotinamide,

3-quinolinecarboxamide, 4-isoquinolinecarboxamide or the like.

(3-Quinolinecarboxamide and 4-isoquinolinecarboxamide can be prepared in the conventional manner, e.g. by treating corresponding acids with ammonia). Other process variations will be obvious to those skilled in the art, in particular from the teachings referred to in the international patent application

CT / US83 / 30725, cited above.

One of such alternative routes to Scheme 1 is shown in Scheme 2. In the first step of Scheme 2, the alcohol reagent (prepared by reaction of 2-iodoethanol with nicotinamide) may contain a shorter or longer alkylene bridge. And the pyridinium moiety may be substituted by an equivalent pyridinium vehicle prepared in an analogous manner. Thus, for example, in the first step, an alcohol of the general formula

(CH ₂ ) _r OH

wherein n is an integer from 1 to 8, preferably from 1 to 3,

30C00

w

3σ οα

with a compound 2 or with another chelating agent containing a trifluoromethyl group or a precursor thereof. Alternatively, an alcohol of formula

(prepared by reaction of nicotinic acid with 1,2-propylene glycol in the presence of dicyclohexylcarbodiimide) or a corresponding positional or homologous isomer or derivative thereof of the quinolinecarboxylic acid or of an isoquinolinecarboxylic acid may be quaternized, by reaction with methyl iodide, and use it instead of the alcohol reagent shown in scheme 2. Still as another variation, bromo glucose may be reacted with nicotinamide, picolinamide or isonicotinamide or a suitable quinolinecarboxamide or isoquinolineearboxamide to give a alcohol, Compound Initial, Formula,

which can be used instead of the alcohol reagent used in the first stage of Scheme 2. Still other variations can buy '' - H vu ₍ 'Ufvu!

the reaction of nicotinic acid or another suitable acid containing a pyridinium nucleus with a suitable di- or polyhydroxyl compound such as ethylene glycol, propylene glycol, inositol or a single sugar, the coupling of the resulting intermediate through its (s) to the carboxylic acid group of the chelating agent or precursor thereof and quaternizing the intermediate therefor.

The foregoing schemes 3 are illustrative of the type of

used to prepare compounds in which the linkage between

the vehicle and chelate moieties are made through an ami group

or hydroxy in the chelating agent or precursor thereof. The ester

activated nicotinic acid, 16, may of course be substituted by

by an activated ester of this acid or a

containing a pyridine nucleus. The activated esters equi

%

is replaced

brave, for example. an ester in which the group is a group

0 ^ "

or

NO ₂ (especially p-nitrophenyl),

are well known to those skilled in the art. The preparation of such esters is carried out according to known techniques, e.g. by reacting the acid chloride or acid anhydride in the presence of dicyclohexylcarbodiimide (DCC) with N-hydroxysuccinimide or another compound having an alcohol function, thereafter quenching the product, for example with methyl iodide or with sulphate of dimethyl.

Scheme 5 illustrates another possible route when the connection between the vehicle and chelate moieties is through a

hydroxy group in the chelating agent or precursor thereof. The first phase of this, this sequence is described in the patent, U.S. 4,444,690 issued to N ² Fritzberg; the resulting ethyl ester 30 is then reduced to the corresponding alcohol using an appropriate reducing agent, e.g. lithium aluminum hydride. Thus, the reduction introduces a -CH 2 OH group instead of the acid group into compound 2. Other chelating agents containing a -CH 2 OH group or precursors thereof may be converted into the corresponding compounds containing a group -CH2 OH, from which the carrier-containing moieties may be obtained as derivatives, as described above generally. There is indicated in Scheme 5 a

of these derivative formations. Conversions 31 ->3.2> 33

-> 3k are identical to the reactions indicated in Scheme 2 above

as well as in the Fritzcerg patent. The moiety containing the carrier can be easily introduced into the structure, after obtaining compound 34, by a wide variety of processes, using the activated quaternized ester 12, used in Schemes 3 and 4, or other activated ester; or by reaction with bromoacetyl chloride and further reaction with nicotinamide, isonicotinamide, 3-quinolinecarboxamide, picolinamide, 4-isoquinoline carboxamide or the like to provide compound 36 or an identical derivative. Subsequent reduction to the dihydropyridine form as described in the text and in the PCT / UE 3 / O 725 patent application may be effected separately, or, preferably, it may be carried out at the same time as the reduction of the technetium to an appropriate oxidation state.

Scheme 6 illustrates a process which is used in particular when the connection between the vehicle and chelate moieties

is made through an -NH- group which is part of a

JUSUU

' ^Z ^ S' ·· *

ΤΒ1ΗΤΛ ESCUDÔ

meadow or d ©

an imide or a primary or secondary amine with a very low pha. The conversion of an ester group into the corresponding amide is effected with excess ammonia. Then, the chelating agent precursor 42 is subjected, a -CQKEL functional group, N-hydroxyalkylation, e.g. by reaction with a Zn aldehyde, formaldehyde, benzaldehyde, acetaldehyde or chloral (b) in such a way, for example, in the case of chloral, the group -CONYL is a function,

Cl-JC-CHQH

³ I

CONH

thereby forming a suitable bridge group. The resulting compound is then subjected to any of the procedures described herein or in the above-mentioned PCI patent application for the attachment of the carrier to a hydroxy-OH group. One such process, i.e. the reaction of the alcohol with nicotinic acid in the presence of dicyclohexylcarbodiimide, is indicated in Scheme 6.

Scheme 7 is illustrative of a process wherein the group

to which the vehicle is to be connected is part of one. imide. The first stages of this Scheme are described in. Eritzberg patent mentioned above. Thereafter, the compound 51 is reacted with excess ammonia to give the corresponding succinimide, which, when heated, loses ammonia to give the succinimide 52. This intermediate is then reacted with an aldehyde, for example in the manner described generally in the previous paragraph and a derivative of the resulting group containing a hydroxy group is also prepared as described above.

Scheme 8 further illustrates, another alternative for the

Uses 1 and 2;

3,4-Diamino-benzoic acid is described, on p100

Q ESOUP 5

Fritzberg, as an initial compound for the preparation of chelating agents. Scheme 8 utilizes the reaction sequence of Scheme 2 and may vary in any of the many ways described with respect to Scheme 2 above. In addition, the compound 59 may be optionally subjected to the reactions set forth in Schemes 5 and 6 and / or described in connection with those Esters; i.e. the carboxyl group -COOH can be converted into a -O ₂ θ ₂ or -CO ₂ group and then derivatives thereof, as indicated and described with respect to the same Schemes.

Schemes 9? 12 and 14 illustrate the typical conversion of a carboxylic acid ester group into the corresponding amide (-CONH ₂ ); reduction of the amide group to give the corresponding amine (-CH ₂ NH ₂ ); the reaction of the amino group (-WH ₂ ) with a nicotinic acid ester; quaternization with methyl iodide; and reduction of the corresponding quaternary compound of formula I to give the corresponding dihydro compound of formula II, or conversion of the compound of formula I directly to the radioactive compound of formula III. These processes may vary as discussed with respect to Schemes 3, 4 and 5 above.

ores.

Schemes 10 and 15 given above illustrate the typical conversion of an alcohol (-C (b) OH, which can be obtained from the corresponding carboxylic acid ester, to the corresponding nicotinoyl ester; reacting the ester derivative with methyl iodide to give the desired quaternary compound of Formula I; and reduction to give the corresponding dihydro compound of formula II or the direct conversion to the corresponding radioactive drug of formula III. For process variations, see the discussion of Schemes 3? 4 θ 5 above.

101

, 30500 æ 30500

"i"<j4hg

(I.e.

shields i; JSC

A typical process for introducing a longer alkylene chain between an atom which is involved in the formation of the chelate and a pendant amino group (-NH-) to be attached to the vehicle moiety is indicated. As indicated in this scheme, a secondary amino group

/ NH with a halogenoalkyl, e.g. For the substitution of the hydrogen atom of the group by the group -CH2 CONH2. Reduction of the amide provides the corresponding compound / HCEâ,ƒCNâ, ".

This amine can then be reacted with an activated ester of nicotinic acid and quaternized and then reduced as indicated in the other schemes. For variations, see especially the Esque

but 3, and 5 above.

Schemes 13 and 16 further illustrate other processes for the elongation of the alkylene chain, in which case the chain is inhaled by one or more oxygen atoms. Thus, a -CH-OH group is typically converted to the corresponding lithium salt and this is then reacted with an iodoalkanol, e.g. ICH-CH-OH, to convert the -CH ₂ O-Li ⁺ group into a -CH ₂ OCH ₂ CH ₂ OH group. It is evident that the chain may be stretched using a longer chain iodoalkanol, or by repeating the two steps to be described (in which case other intermediate oxygen atoms) should be introduced. The -CF 2 OCH 3 -C 4 H group is then converted to the corresponding nicotinic acid ester, which is then quaternized to give the desired quaternary salt. Also, in this case, the reaction schemes may undergo variations as discussed in connection with Schemes 3 and 5 above.

In Scheme 17, the reaction of an amino group -NH ₂ with an activated ester of nicotinic acid and the quaternization is reported to be about 30.00 to 30.00

Eur-lex.europa.eu eur-lex.europa.eu

Rsy; -'Β ¹ * - Τ '<..... * .....- "· *» *

102

IRt

ί ι T-RfftTA £ 3 <3UP & 5

sequential. The resulting quaternary compound of general formula I is then reduced as shown in the other schemes.

Many of the first steps in the reaction schemes described above are analogous to the reactions described in U.S. Patent Specification 4,444,690 to Eritzberg. See, for example, the conversion of compound J7 into compound 30 in Scheme 10; The

conversion of compound 30 into compound 40 and thereof into compound 4-1 in

Scheme 12; the conversion of compound 111 into compound 112, from compound 113 and from compound 114- in Scheme 13; etc.

Scheme 11 above, as Scheme 11 which has already been discussed, shows another typical process for introducing a longer alkylene chain between the nitrogen atoms. Here, the secondary amino group NH2 is converted to the corresponding group

b-CHN-CH-CH-NH _n . The resulting amine was then reacted

<eZ dd <Z

with an activated ester of nicotinic acid and the product obtained is then quaternized and reduced as in the other schemes. As a preferred alternative in this and many of the other reaction schemes described herein, the quaternary chelating agent precursor according to the invention may be prepared directly by reaction of the corresponding amine with a nicotinic acid quaternized activated ester. They will become obvious or after variations, for example. from schemes 3? 4 and 5

before.

Scheme 19 represents another route for the derivatives resulting from the Scheme. 1. Of course, this scheme is varied in many ways, most especially in the fourth stage, where nicotinamide can be replaced by one. another amide (eg one of those listed in Scheme 1) and the compound ICI CC ^ OHOH may be replaced by another compound of the general formula

in which Z 'represents a straight or branched chain C -C-C alquil alkylene group.

Scheme 20 illustrates another route for the preparation of the derivatives of Scheme 8. This scheme represents a particularly interesting synthetic route for the preparation of the protected quaternary derivative 62. In addition, intermediate 17.6 may be varied as mentioned in connection with Scheme 19; also this process may be adapted to the preparation of derivatives of other chelating agents containing a carboxyl group (-COOH); for example those of Schemes 1 and 2.

In Scheme 21, intermediate 179, used in the manner described in Scheme 20, is used to prepare further compounds according to the invention,

3,4-diaminobenzoic acid.

Scheme 22 is illustrative of a further variation in the art of Scheme 8. Scheme 22 can be readily adapted to the pre-

for the preparation of other derivatives according to the present invention; see, for example, the discussions relating to Schemes 8 and 20 above.

In Scheme 23, two extremely advantageous alternative routes for the preparation of the quaternary salt 76 of the Burn are given. These alternative routes utilize the quaternary activated esters of nicotinic acid to directly prepare the quaternary derivative 76 from the corresponding primary amine 74. The use of the succinimidyl or phthalimidyl (1α or 19.1) quaternary intermediates is illustrated. Other quaternary activated esters will be obvious for use in this reaction from the various processes described herein, for the formation of the quaternary compound of formula I under

104r- SSgUDOS jt 'í ^Esojfcóe!

The process of Scheme 9 may be used to prepare the other derivatives according to the invention.

Scheme 24 further represents another very advantageous route for the preparation of the quaternary salt 76 of Scheme 9. In the especially preferred scheme, a protecting group is introduced before the vehicle function is introduced; the protecting group is then removed before the quaternary group is reduced to the corresponding dihydro group. In the case of the chelating agent indicated in this scheme, the reaction with acetone protects both the secondary amino groups and thiol by forming thiazolidine structures so that those groups do not interfere during the addition of the carrier moiety. Subsequently, the secondary and mercury amino groups are regenerated by reacting the protected mercuric chloride-protected intermediate in an organic solvent such as methanol, preferably at room temperature, and then decomposing the resulting complex with hydrogen sulfide. See, for example, U.S. Patent No. 2 which uses this process for

production of penicillamine esters. After the quaternary salt / 6 is prepared in this manner, the procedure of Scheme 9 may be used to prepare the other derivatives of the present invention. Variations in this technique may be used, e.g. as described above with respect to Scheme 23, to prepare other derivatives according to the present invention.

Scheme. 25 represents another route for the preparation of the compounds obtained by Scheme 14. This process utilizes the preferred route of introduction of the carrier portion in its quaternary form and can easily be adapted to the preparation of derivatives of other chelating agents containing a carboxy group (-C H H) and / or the introduction of other vehicle moieties

30 $ 00 30S00

ίΦ Β® O ^f yYí, w 1L2

fc

Lu

described herein.

Iffcí '

. TR1WTA Ϊ Í í TftíNTA SHELLS ¹ '' ,, · ESPUOOS '

In Scheme 26, there is illustrated a process for joining a group

of formula

ff

-CR2 -N

or a portion of the vehicle

analogous to a primary amino group pendant on a chelating agent. This process utilizes the thiazolidine structure to protect the secondary amino groups and thiol in the chelating agent consisted, as discussed with respect to Scheme 2U above.

Another route for the preparation of the derivatives shown in Scheme 26 is depicted in Scheme 27, wherein the primary amine group on the protected primary amine is first converted to the corresponding group of the formula -KHCO-R 2 -Br, which is made then reacted with nicotinamide or the like to give the protected quaternary intermediate.

Scheme 27 represents a process for the preparation of vehicle-containing derivatives of yet another type of chelating agent. The desired chelating agent, in this case, contains chelating groups which are introduced after the quaternary form of the carrier has been attached. The preparation of yet another type of chelating agent is shown in Scheme 29.

Where sirayl schemes are indicated for the preparation of the other derivatives according to the present invention. The phases of

introduction and removal of protecting groups are only included where necessary. The order of the phases can also be changed; most especially, the quaternization may occur earlier in the reaction scheme, depending of course on the compounds in question. Other reactive schemes, reagents, solvents, reaction conditions etc. will become perfectly obvious.

.}

for those skilled in the art. Also, with regard to the

'ï. Wg, W '·

TR1WTA! ^!

E50UD06 i SHIELDS

When an anion other than that obtained is desired, the anion in the quaternary salt can be subjected to a

anions, using an anion-exchange resin or, more suitably, using the method of Kaminsky et al., "Tetrahedron", Vol. 34, 2857-249 (1978) According to the naminsky et al. a methanolic solution of an acid of formula H com will be reacted with a quaternary ammonium halide to afford the methyl halide and the color X quarternary salt

respondent.

The reduction of the quaternary salt of formula I to give the corresponding dihydro derivative of formula II may be carried out at a temperature in the range of about -10Â ° to room temperature for a period of time of about 10 minutes, conveniently at atmospheric pressure. A large excess of reducing agent is generally used, e.g. a molar ratio of reducing agent to the starting compound of formula I of 1; The process is carried out in the presence of an appropriate reducing agent, preferably an alkali metal dithionite such as sodium dithionite or an alkali metal borohydride

such as sodium borohydride or lithium aluminum borohydride, in an appropriate solvent, it is convenient to carry out reduction with sodium dithionite in an aqueous solution; the dihydro product of general formula II is in fact water-insoluble and can therefore be readily separated from the reaction medium. In the case of reduction with sodium borohydride, an organic reaction medium, e.g. a lower alkanol such as methanol, an aqueous solution alkanol or other protic solvent. However, more typically, the quaternary compound of formula 1 is reduced therein

The reaction mixture used in

reauao

of technetium

a state of

TRIHTft ezs

j. cVoiJPgy] [E50UOOS_J

oxidation, the radioactive drug of formula III being obtained, in one step, from the quaternary compound of Formula I. Further details of the reduction in one phase are given below.

It will be apparent from the foregoing disclosure that in accordance with the present invention a wide variety of derivatives of formula I can be obtained through the compounds of formula IV. However, in an especially preferred embodiment of the present invention, novel chelating agent precursors of the general formula,

τη k / i

5 \!

RC

5 ι R

HS

t

CR,

5 ^ c

z \

5 ΗΝγ_? Ή Q '

C "Ό

V

Rz ^z

.

bad

(Ia)

in which each R 2, independently, represents a hydrogen atom or a C 1 -C 4 alkyl group, or a R 4 can be associated with the group of formula

y C-P _r such that the group of formula

ral

represents a group C = O; each symbol

Independently of one another represents a hydrogen atom or a C1-4 alkyl group, or a R4 may be a

with the group of the formula / CR2 adjacent in such a manner as Rz

\ / 6

that the group of formula C represents a group

, ^And 6 \ \ /

## STR2 ## wherein X represents a radical of formula

\

HN

/

NH

/

7 \

30S00;

TlHMT * TlHW-TAf ESOUOOS i. ESffUDOB

RN

w

z

:H

or

0 ⁼ C j, r C ⁼ O Z "QC ⁺ J

? ₇ R ₇ R _? (alk) -A '-Z * QC J,

7 7 7 s (all) s-A '- / W

wherein each R4 is independently hydrogen or C1-4 alkyl; (alk) represents a straight or branched chain (C -C-C)) lower alkylene group, which may additionally contain 1.2 or 3 oxygen atoms in the ring. chain, said oxygen atoms being non-adjacent to each other and also being non-adjacent to the group represented by -A '; k and n are as defined in formula I; m 'represents a number which, when multiplied by n is equal to 1; q represents zero or 1; -A- represents an oxygen atom (-O-), an -NH-, -COO- or -CONH- group, or a group -NH-, in which Eθ represents a

or a group -CON-, in which R1 is

Rf

C 1 -C 4 alkyl; when -A 'represents an oxygen atom, an -NH- group or a group of formula

-N-, £ QC ⁺ J is a radical of any one of s is ^E

(a) to (j) above; when -A 'represents a -CONH- group or -CONH-

or when HN

/

(I) has the above-mentioned imidazole structure, J represents a radical of any of the above formulas (k) to (s); and when -A'102

represents a -COO-, QC ⁺ group represents a radical of any of the general formulas (i) to (xiv) above.

The salts of the general formula Ia preferably have the partial structure

HC

* - | o = c

CH.

i-L-0

:H

HC,

3

HC

^ά \

HR

HS

\ / 3 ° ^Η

X

NH

^C ?

. ^X CH. CH _n ³

or hC H ₂ C

SH

HS

HN

/

NH

iH.

I *

CH

or are position isomers and / or homologues of the first two indicated partial structures. It is also preferable that, when

HN

/

NH

represents a group of the formula HNHH

Rr? R (Ry) (alk) _c -A '

- / ζχΐλ

eads R? to represent

a C1 -C4 alkylene group or a C1 -C4 alkylene group unsaturated by an oxygen atom in the chain; and that, when

\

HN

/

NH

represents a

(alk) _s -A '- /

(alk) is preferably a C₁-C₄ alkylene group or an alkylene group of _C1 ^ interrupted by an oxygen atom in

chain, when any of the groups referred to above, the values presently

HR NH represents

sc n

Preferred for the group (alk) -A ¹ - are -COO-, s

-CH? -CONH-, -O- -CH.HH- and -CH.OCH.CH _9, Preferred values

<2 dc is. W.

^; 30500 | 30500

Tbinta i

(I.e.

7th there is

|

for J in the general formula Ia defined above are those indicated with respect to general formula I.

The novel preferred chelating agent precursors of formula Ia are the novel chelating agents of the general formula

n ^SH A ι

¹

R.-C

5 ι

R,

NH

HS _R

1 / O

GE I ⁰

Faith

l

.

in which R1. and R6 are as defined above for

, ⁷ /

general formula Ia and HN NH represents a radical of general formula

wherein R ^, (alk) is -A ¹ - are as defined above for formula Ia; when -A ¹ represents an oxygen atom, an -NH- group or a group of formula

in which R 2 represents a C 1-4 alkyl group,

Rg

/ TR-HG J is a radical of any one of formulas ⁽¹⁾ to (j ') mentioned above, when -A ¹ - is a -CONH - or a group of the formula -GON-

^E 9

By B represents an alkyl group or, when the

of the general formula HN NH has the structure

Preferred hereinbefore, the group of the formula (ZTHC) is

moiety of any of formulas (k ') to (s') mentioned above, and when -A ¹ - represents a -COO- group, then / "DHCj ⁷ is a radical of any one of formulas (I') The preferred compounds of formula Ila are dihydro derivatives which correspond to the preferred compounds of formula Ia.

Also preferred are novel radioactive drugs wherein a compound of formula Ia forms a complex with a radioactive metal, especially with a synthetic metal. Especially preferred radioactive drugs have the general formula,

(ϊ 118-)

in which B 1 and B 2 have the meaning given above for

Ia and N

represents a radical of formula

the general

\

H

or 0 = C

TJ

c = o

in which alk, if -A'- have the meaning defined above for the general formula Ia and Z 'has the meaning defined above for the general formula Ila;

and corresponding quaternary forms, "retained" in the brain, especially those of technetium, having the general formula,

in which R _e , R z, m ', Z "and n have the meanings defined for ^{j 0} .

\ z

the general formula Ia and Π

represents a radical of

general formula

/

Q '

(I.e.

NN

w

or 0 = GC = 0

(alk) _and -A'-Z "QCÍ7 / \ C ⁺ y

-alkyl, - and R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2 and R ² are as defined above for the general formula Ia.

Preferred complexes of the general formulas IIIa and IVa are. those corresponding to the preferred derivatives of general formulas 1a and 1a.

Precursors of chelating agent, chelating agents and radioactive drugs within the scope of the present invention may also be prepared by reaction of a compound 17 with

a compound 2% according to the reaction scheme,

113

Thirty

ESCUDUS

or

iZ

xs.

d

ethanol or methanol

0

CH.

and further reaction of the amino group of the 2% compound obtained with the carboxyl group of compounds such as the 2-oxopropionaldehyde-bis (thiosemicarbazone) derivatives having a free carboxyl group.

Illustrative of such compounds is 3-carboxy-2-oxopropionaldefdo-bis (N-methylthio-semicarbazons), a bifunctional chelating agent described by Yokoyama et al. in U.S. Patent 4,287,324. Chelating agents which contain a carboxyl group of Yokoyama et al may also form derivatives as described above generally for the preparation of derivatives of carboxyl groups, as set forth in Schemes 1 and 2. In addition, Yokoyama et al. chelating agents of general formula

LOL

I ¹ li

HOOC-CC = MH-C-HH-

R.,

£

R ₀ -CN -H-C-

W

in which Bp Rp and Rb are each a hydrogen atom or a

can first be converted into the corresponding esters

in

(per

(3H, s)

k; « _Ftillllt

there -

Spanish

ex. substituting the -COOH group -COOC H -), which can then be reduced to give the corresponding alcohols (replacing -C0QCJ3 _c by _the group -CH 0H) or converted to the corresponding amides; the alcohols or the amides can then be converted into the corresponding vehicle-containing derivatives;

see, for example, the discussion of Schemes 9 to 16 above. Other process variations will become apparent from the many reaction schemes mentioned above.

Another bifunctional chelating agent which can be readily converted into the chelating agent precursors containing a redox system, chelating agents and radioactive drugs according to the present invention is a compound of formula

which is also known as amino DTS and which is described in the literature, e.g. was "J. J. Ducl. Red." 1Q, 610 (1982). 0 aaino ^r TU can be converted easily into derivatives according to the present invention, by reacting it with an activated ester of nicotinic acid or the like and quaternizing the resulting ester to afford the corresponding precursor of formula I, which may then be used as generally described herein to prepare the corresponding compound of formula I and the radioactive drugs of formulas III and IV. See, for

For example, Scheme 30 below.

ijuauu

Χ &Χ'Χί

30:00 to 30:00

ι_ΐ5

(I.e.

Α "ο Λ *» ^{τ Λ} _and V _and 'grape

Yet another group of known chelating agents which is especially well suited for conversion into chelating agent precursors containing a redox system, chelating agents and radioactive drugs in accordance with the present invention may be represented by the general formula,

^3x N (CH) .J Vc = K - RH-C-RHR. X ^{2 21} I

4 C = R-HH-C-NHR,

I II

fc

U- ₃

wherein R ^, B ^, and R ^ each represent a hydrogen atom or an alkyl group b - ^ - en ^ G ¹ represents an integer from 0 to 3.

See, for example, U.S. Patent 4,511,550 to Yokoyama et al. and Australian Patent Serial No. 533 * 722. Especially preferred agent encompassed by this group is known as amino-RTS, or ARBK, and has the formula

H CH _O c * d.

RH-C-RHCH.

bH-C-RHCH3,

The amino-PTS can be converted into the derivatives according to the present invention through the activated ester, as described above with respect to the amino-DTS. See, for example, Scheme 33 below. The exact structure of the resulting technetium complex

224 was not determined; it is possible that the C

T to P ₌ c

; (I.e.

are also reduced during one of the reduction phases. A possible sequence for complex 224 is as follows:

(A similar structure may be indicated for the 16% complex of Scheme 30).

A preferred alternative route for the preparation of amino-PTS, amino-DTS derivatives and the like is illustrated by Schemes 31 and 32 below. Using this route, a quaternized activated ester is reacted with the binder containing a primary amine group to prepare the quaternary chelating agent precursor of Formula I in a single step. From the discussion of a large number of the reaction schemes mentioned herein, variations in this extremely advantageous single phase, as well as in the two alternative phases indicated in Schemes 3θ θ 33, will be evident. It should also be noted that the introduction of by the formation of a carrier in its quaternary form, typically through a quaternized activated ester such as ester 19.1 or 1 ', is generally advantageous over the two-step process and any of Schemes 6-7 and 9-17 mentioned above can be easily modified accordingly.

sqmequem

? Trivia

L SHELLS

<

Scheme 3θ

30%

3ο $ οσ,

Jí & OZ ^'1' Λ '4'

117

WraMba

ZK-CH = C

is.

X

H

3

^or C-RHCH

CH, ΔΉ -u-NHGH,

XZ is ^J /

16

CR, NH-G-NHCH,

.

G = N £

/

= C

\

C = K

GH

NH-C-1BCH

W

A compound as described in, for example, Gap, J. Org.

1%, 61C (190%) J

162

CH, I 3

0

GNR-GH = C

R, C .ZH-C-1ECH>

3

G = G

zx

II

kz

1,

163

Ic-99m pertechnetate reducing agent, eg Γθ2 2 2θ% ^{e a} alkaline

U Qr

TcO complex with reduced form of redox system

I65

Will rustle go: alive

reduction agent 'oTcG,

(I.e.

GNH-CH = C

-Ql ·

quaternary drug value

radioactive "retained in the brain"

reduction eg with Ha. SiO2, in an alkaline medium

CH.

HH-C-HCEEC:

GH

tC-HCl.

X \

Ui

, -O

(I.e.

ν

γ

or

And

(I.e.

And

(I.e.

And

I

οι = ο

ι

And

f

And

(I.e.

35

R-H

I

• \ "

I

ΜγΗ

-o

I-I

041

CJ

i

And

(I.e.

I

Οτ «

V-:

(I.e.

I

8i ω C 1 -Ρ Ο.π3 «

~ α, ω Ο - · Ρ +3 · C0

Η Ε Ω »

P

Ο ι-1 © ω C Θ Ο Ο ΐΛοα © IT \ OJ. [S01 Ki I-1 ·

SH in the co \ r> 5 · ν>

- - - - - - - - - - - - - - - - - - - - - - - - - - - - -

fij Ω, © Si ra g pp ώ ΰ ra SN © 3 3 © 43 <

E4

i

W

04

(i.e.

"η

(Μ |

0J

faith

the

+3

X

2 o Ο "Φ © (D í-l

M Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή Ή

The title compound «5 -Hl« σ> ι

(I.e.

ι αι

C · Η |

ω

ΰ c C

> ί-ί C0 · Η Ε · Η +3 (D

Ο Ρ \ 0 cd '© ECO Sd · Η © ^f O =

• μ cs ο

C0 Ρ-ι ΐ 3

σ

Ee

ω cc · Η

is

Sh Ρ φ c'co 8)

(2)

04l

.Μ

Scheme

121

^! 30 $ 00 ^! 30 30 $ 00

. Α Α Α Α Α Α Α Α Α Α Μ Μ

. • JS? jf

Tító, 4w

T RJ MT Aj ESSVPOSíor a dwarf way * LO to the presently considered car system can be incorporated into the structure of a new radiopharmaceutical of teenéeio-99m whose chelate portion is the residue of an iminodiacetic acid, amino-or hydroxy -substituted, e.g. (1-naphthyloxy) -2-hydroxypropyl] iminodiacetic acid. These substituted iminodiacetic acid chelating agents are known and described by Loberg et al. in U.S. Patent No. 4,017,596; these chelating agents can be protected to the required degree and then introduced the trigonellinate or other carrier structure upon reaction with the amino or hydroxy group on the chelating agent. dog.

In an analogous manner, suitable chelating agents and their precursors which contain a dihydropyridine salt of the pyridinium carrier system may be prepared by reaction of compound 17 or the like with a chelating agent, which is an alkyl-substituted monophosphonic acid such as amino butylphosphonic acid, 1,5-diaminopentylphosphonic acid and the like. Chelating agents of this general type are also known and are illustrated by those described by Rufler et al in U.S. Patent 3,976,762.

Other chelating agents containing one or two carboxyl groups are further described in U.S. Patent 4,444,690 to Fritzberg et al. Vehicle-containing chelates containing vehicle corresponding to the Fritzberg chelates can be prepared as described above in general and as shown in Schemes 1 and 2 mentioned above.

U.S. Patent 4,444,690 to Fritzberg discloses an interesting series of chelating agents

of 2,3-bis (mercaptoalkanesamido) -alkanoic acids of general formula,

R '

HS-CH-CO-NH-CX I

HS-CH-CO-KH-C-COOH

R '

in which X represents a hydrogen atom or a carboxyl group and R and R 'each represent a hydrogen atom or a lower alkyl group,

and their water-soluble salts, used to prepare the corresponding radioactive drugs of formula

in which X represents a hydrogen atom or a carboxyl group and E and R 'each represent a hydrogen atom

or a lower alkyl group.

The Fritzberg chelating agents are prepared from the corresponding β-3-diaminoalkanoic acids by esterification with a lower alkanol containing dry hydrochloric acid and subsequent reaction of the resulting alkyl ester with. a chloroalkanoyl chloride to give the bis (chloroalkanamide) ester,

reaction of this ester with sodium benzoylthiolate

0

II

CSK

The;

and alkaline hydrolysis of the 2,3-bis (benzoylmercapto) ester, 30% -30%

m.p. iWrWi?

, 1 '''', 1 '''',

. Λ Ι Ι Ι ...... ...... U U U U

jjX ^f *

JníiWU !! t__. Siiuhi.

.

X * _: Tm # **, cscueoe

dimethylamino) -alkanoic acid

produce the 2,3-di (mercaptoalkanoamido) -alkanoic acid chelating agent. The preparation of an analogue from 3,4-diaminobenzoic acid is also described by Fritzberg. Many of the Fritzberg synthesis steps can be adapted to the production of the derivatives of formula I according to the present invention in which, instead of the carboxyl group in the Fritzberg chelating agent, there is a (alk) A'-Z "in which the structural variables have the

fc>

as defined above for general formula Ia. See, for example, Schemes 12, 13 and 16 mentioned above.

0s radioactive pharmaceuticals which contain a dihydropyridine pyridinium salt carrier system can also be prepared using a novel precursor to Ente chelating obtained by reacting, in pyridine as solvent, the compound 2¾ mentioned before with nitrllotrlacético anhydride according to the ger technique »l illustrated in known Kunn et al., US patent 4 ^Q · M .4-13.206.

The dicarboxyl-pyridinium salt resulting from the previous reaction is obtained in pure form in the following manner: The volatiles are evaporated from the reaction mixture on a rotary evaporator to give an oily semi-solid residue. A 10% (w / v) aqueous solution of sodium hydroxide is used to dissolve this semi-solid oily residue. The resulting solution is extracted with methylene chloride to remove the remaining pyridine from the aqueous phase. The pH value of the aqueous phase is then lowered. up to about 6-8. The volume of the resulting aqueous solution is reduced to about the volume of the original pyridine solution and about five times this volume of a saturated picric acid solution is added to give a picrate derivative precipitate.

124 ·

K Tft-N-tfi

This picrate precipitate is washed with cold distilled water and then dissolved in a 10 X (v / v) aqueous hydrochloric acid solution. The resulting solution is extracted with methylene chloride until no yellow color is observed in the aqueous or methylene chloride phases. The resulting colorless aqueous phase is concentrated to about the volume of the original pyridine solution and is then freeze-dried to provide the chelating agent in dry form. The dry chelating agent is dissolved in ethanol and precipitated using the diethyl ether coupling technique

described below in Example 4.

There may also be prepared a further

chelating by reacting equimolar amounts of ethylenediaminetetraacetic acid and acetic anhydride in pyridine

anhydrous in accordance with the technique described by Nunn et al., patented U.S. Pat. And then reacting an equimolar amount of the compound to give

monoamide addition product. The tridentate chelating agent salt is obtained in the manner described immediately above.

Then, it is reacting the tridentate chelating agent precursor salt so obtained with pertechnetate ion 99ni described below in Example 5> ⁰ which reduces both the teenécio as the pyridinium salt to provide a drug delivery system 1: 1 radioactive metal ligand / ion complex according to the present invention. The complex so formed is ionically neutral as the five valencies of the reduced technetium-99m metal are met with one oxygen atom and the oxygen atoms of three carboxylate groups and the pyridinium nucleus is in its reduced dihydropyridine form.

tome was mentioned before,

preparation of the precursors of

; 30 οα '3θ οα!

^t

Μ .., 1. ,

125

eur-lex.europa.eu eur-lex.europa.eu

IS* ' ·

Tujmta

ί ... ifUNTA f>. THIRTY E5OU.QOS ₍ SCIÓOS

chelating agent, chelating agents and radioactive drugs according to the present invention should be planned in relation to the starting compounds in question, in particular as regards the presence of reactive functional groups besides the group to be connected. portion of vehicle. The stage in which the

vehicle is entered and the way it is entered will be determined accordingly. Alternatively the carrier should be introduced in quaternary form at an early stage of the synthesis as illustrated above. When this is not required, it may be more advantageous to react an appropriate starting compound such as nicotinic anhydride with a binder precursor or a binder precursor containing an amino or hydroxy group and quaternize at a later stage upon attachment of the binder of chelation) with the 3-pyridinecarbonyl group.

The processes described above are only intended to be illustrative. For example, many variations can be made on the complexing moieties of the molecule and such variations may of course effect the synthesis scheme, in particular as regards the need for the introduction of protecting groups and their subsequent elimination.

In order to better illustrate the present invention and its advantages, the following specific examples are set forth, and it is to be understood that they are intended to be illustrative and not limiting in any way.

Example 1: N- (Butoxycarbonyl) -N- (2-mercaptoethyl) glycyl- ^1- (2-aminoethyl) homocysteinamide (Compound 14 of Scheme 3)

The tert-butoxycarbonyl) -N-2- (methylethyl) -glycyl-homoeysteine-thiolectone (.13) is prepared according to the des30 θα 30%

E5CUQGS

crita in Examples 1 and 2 of patent US 4,434.151 invention ^ττ 2, E ^ rne et al., and dissolve 1.0 g (3 mmol) of this compound in 25 ml of tetrahydrofuran (ΪΗ?). The resulting solution is cooled to about 0 ° C and 1.3 g (30 milliliters) of ethylenediamine is added to form a new solution. The resulting new solution is allowed to stand for about one hour. The volatile components of the solution are then discarded on a rotary evaporator. About 10 ml of n-butanol are added. the anhydrous solution is added and the liquid components of the solution are again discarded. composition by rotary evaporation. The last phase is repeated until the vapors remaining in the evaporation vessel do not indicate an alkaline pH value on a moistened pH indicator paper, thus showing that ethylenediamine has been substantially eliminated and that II- (butoxy-tert-carbonyl ) - ?? - (2-mercaptoethyl) glycyl ^K-1 - (2-aminoethyl) -homocisteínamida thus obtained is substantially pure.

Example 2a: Succinimidyl nicotinate (Compound 16 from

Scheme 3)

12.3 g (0.1 mol) of cyclic acid and 11.5 g (0.1 mol) of N-hydroxysuccinimide are dissolved in 300 ml of hot dioxane. The mixture is cooled in an oil bath and 20.6 g (0.1 mole) of dicyclohexylcarbodiimide in 30 ml of dioxane is added. The reaction mixture is stirred, with cooling, for about three hours; then cooled in the refrigerator for at least 2 hours. The precipitated dicyclohexylurea is removed by filtration, the solution is concentrated in vacuo and the solid products are precipitated and recrystallized from ethyl acetate. 14 g of succinimido nicotinate are thus obtained under a. for

12?

bad. of white crystals. (Product yield is confirmed by RUM.

63.6 X). The structure of the

Example 2b: Succinimidyl trigonellinate (Compound 17 of Scheme 3)

33Âμl (15 millimoles) of succinimidyl nicotinate are dissolved in 50 ml of dioxane and 3.4 ml (3.2 g, 60 mmol) of methyl iodide are added. The reaction mixture is heated at reflux for about 48 hours. The yellow crystals which precipitate during the reaction are separated by filtration, washed with ethyl ether and dried in vacuo at 40 ° C. Succinimidyl trigonellinate (Yield: 96.3 g) is thus obtained. The structure of the product is confirmed by NMR.

An improved process for the preparation of Compound 17 is as follows:

A solution of 9.0 g (41 mmol) of the ester 16 and 11.6 g (8 mmol) of methyl iodide in anhydrous dichloromethane was heated in a pressure-resistant vessel under argon for 16 hours in 40 ml of anhydrous acetone. Filter to remove the resulting smsrel precipitate, yielding 14 g of Compound 17, which darkens to 170øC and melts at 197øC.

Example 3: 1-Methyl-3- (2-U-ethyl) -carbamoylpyridinium N- (2-mercaptoethyl) -glyl-Z-iodide (Compound 18 from Scheme 3)

1.12 g (0.003 mole) of tert -butyl-N-tert-butyldimethylsilyloxy-N '- (2-aminoethyl) (Compound 14) and 0.70 g (0.0025 mole) of succinimidyl trigonellinate - Compound 17 - in 25 ml of anhydrous pyridine, with stirring

tion. An Eean-Stark "micro-separator" and a suitable size condenser are connected to the reaction flask, the solution is warmed to 80 ° C and held at this temperature until substantially all the succinimidyl ester. I deleted

Is pyridine evaporated over an evaporated? rotary, using butanol n. as a pulling agent as described above for the removal of ethylenediamine. Once the pyridine is removed, the residue is triturated with tetrahydrofuran and the solid product is removed by filtration and washed several times with tetrahydrofuran, being careful not to dry it by aspiration of air. The solid thus obtained is dried

*

(2-mercaptoethyl) -glycyl-1-methyl-3- (LN-ethyl) carbamoyl-N, N -dimethylcarbamoyl- pyridinecarboxylic acid.

Example 1 1-Methyl-3- (2-N-ethyl) carbamoylpyridinium] homocysteine (Compound 19 of Scheme 3) K- (2-Rercaptoethyl) glycyl-

if tissolve, with stirring, 1.24 g (0.002 mol) of N- (tert-butoxy carbonyl) ^T -T - (2-mercaptoethyl) glycyl-N '- /' i ° deto-methyl-1 3- (2-N-ethyl) -carbamoyl-pyridinium-7-homocysteine hydrochloride In 16 ml of absolute ethanol, the solution is cooled to 0 ° C in an ice-water bath. Is bubbled hydrogen chloride gas for 15 minutes through the solution and stirred, then the ITA _and for a further 15 minutes. Add 200 ml of diethyl ether to the solution to precipitate the salt. The precipitate is collected by filtration and washed with diethyl ether taking care not to dry the precipitate by suctioning the air. The solid product is then dried in vacuo to give

129

n-Cz-mercaptoethyl-glycyl-N'-Z-1-methyl-3- (2-K-ethyl) carbamoylpyridinium iodide as the cysteinamide.

Example 5: Compound of N - (2-mercaptoethyl) -glycyl-N ^, -Z-ethyl-3- (N-2-ethyl) -carbamoyl-1,4-dihydropyridyl) -homo-cysteinamide and the oxymethoxy-99m (Compound 20 of Scheme 3)

29 mg (0.17 mmol) of 1-methyl-3- (2-N-ethyl) carbamoylpyridinium bromide, N - (2-mercaptoethyl) glycyl-N- ¹ -iodo-Compound In 1.0 ml of absolute ethanol and 1.0 ml of sodium hydroxide solution are added. 1.0 ml of Tc-generating eluent (5 to 50 milliCuries) is added in physiological saline. Is then added 0.5 mL of dithionite solution, prepared by dissolving ^ 33 mg of sodium dithionite Za ^ C ^ o ^) ^r ° P l ^TO im ^RFL solution, sodium hydroxide and heated 0N the mixture sufficiently to reduce the technetium and the pyridinium salt and to form the complex between: ^T - (2-msrcaptoetil) glycyl-D'-Zl-methyl-3- (N-ethyl) carbamoyl-l, 4- dihydropyridyl] homocysteinamide and the oxo-99m ion. The complex thus prepared is buffered by adding 1.0 ml of hydrochloric acid 11 and 4.0 ml of 0.1 molar solution of monosodium phosphate,

Example 6: Compound I: - (2-mercaptoethyl) -glycyl-N'-Z-methyl-3- (N-2-ethyl) -carbamoyl-1,4-dihydro-quinolyl Z-homocysteinamide and the oxotecnate-99m ion

A radioactive drug associated with a vehicle based on a reduced dihydroquinoline carrier can be prepared as the title compound according to the steps outlined in

30 $ 00 - 30500 '

(i.e.

. 1 ®. .

........

SHIELDS}, SHIELDS

examples 1 to 5? but replacing the nicotinic acid in Example 2a with an equivalent amount of 3-quinolinecarboxylic acid

co.

Example 7. O - [(2-Aminoethyl) -homocysteinaffide (Compound 25 of Scheme 4)] -

1.0 g (3 mmol) of N - [2- (S-acetamidomethyl) -mercaptopropionyl} -glycylic-homocysteine-thiolactone (Compound 2 to 4 of Scheme 4), prepared according to art described in Examples 7 and 9 of U.S. Patent 4,454,155, Brenner et al., in 25 ml of tetrahydrofuran. The suspension is cooled to about 0 ° C in an ice bath To a solution of N-Z'2- (acetamidomethyl) -mercaptopropionyl] glycyl-E '- (2-hydroxyethyl) aminoethyl) -homocysteinaffide in a manner substantially similar to that described in Example 1 for the analogous compound.

Example 3: 1-Methyl-3- (2-N-ethyl) -carbamoyl-pyridine-N- (Acetarflidomethyl) -mercaptopropionyl] -glycyl-

(Compound 26 of Scheme 4)

Compound 26 of Synthetic Scheme 4 is obtained in a manner analogous to that used in Example 3 to prepare Compound 19, but the starting materials used are Compounds 17 and 25

However,

Example 9: N- (2-Mercaptopropionyl) -glycyl-N'-Z-1-methyl-3- (2-N-ethyl) -carbamoyl-1,4-dihydropyridine] homocysteinamide complex and the oxotheca-99m ion (Compound 27 of Scheme 4)

Dissolve 0.17 mmol of Compound 26 from Example 8 in

1.0 ml of absolute ethanol and 1.0 ml of 1N sodium hydroxide solution. The complex of this example is then prepared in a manner analogous to that described for the complex of Example 5. Here, the alkaline solution liberates the 2-mercaptopropionyl group from its N-methylene-acetamido protecting group while the dithionite reduces the salts of pyridinium and technetium.

Example 10: 3,4-Dithia-2,2,5,5-tetramethylhexane-1,6-dione

(Compound 68 of Scheme 9)

To a stirred solution containing 115.6 g (1.6 mol) of isobutyraldehyde 67 in 1θ4 g of carbon tetrachloride is added dropwise at 40-50 ° C, 10.0 g (0.8 mol) of sulfur monochloride The addition is carried out in the course of two and a half hours, under a nitrogen atmosphere, occasionally cooling. The solution is stirred at 30-45 ° C with stirring for a further 48 hours under a stream of nitrogen to remove the hydrochloric acid which is liberated. The solution is punctured in vacuo to give 72 g of 3α, 8-α-2,2,5,5-tetramethylhexane-1,6-dione, i.e. Compound 68 of Scheme 9.

^·] Έ BID (CDC1 ₃₎ ^ 9.1 (s, 2-CH0) 1.4 / s-12-C (CH ₃ ^ 7.

Example 11: Ethyl 2,3- (diammonio) propionate dichloride (Compound 70 of Scheme 9)

18 g (0.07 mole)

and cyclohexyl-2-oxime

filtration and taken up in 75 Âμl of hot ethanol at 9Â ° / 0

6 ', 125 ml of absolute ethanol, 15 g of hydrochloric acid gas are added to 1 g of platinum oxide. The mixture is hydrogenated using a Parr hydrogenation apparatus. Hydrogen fixation is complete in 3 hours. The product is separated by filtration.

the ethanolic solution is cooled, the filtrate is cooled and the crystalline product is separated off by filtration. Obtained thus dichloride = 5 2,3- (diammonium) propionate, i.e. Compound £ 0 of Scheme 9. Yield: 35 _z j mp 164-166 ° C (liter 164. 5-165 ° C); BMW (EvO)

b 4.5 (m, 3, - ^T 'CHC0-, -0CH ₂ CH _3); 3.5 (m, 2, -CH H ₂ CH-), 1.3 (t, 3, -OCH ₂ CH ₃ ).

Example 12 5, co-diaza-l, ^{2-dithia-6-etoxicaT,} carbonyl-3,3,10, 10-tetrametilciclodeca-4, D-diene (Compound 21 of

Scheme 9)

Technique I

To 1.0 g (5 mmol) of the bisaldehyde, a solution of 1.0 g (5 mmol) of the ester / 0 and 0.9 ml of pyridine in 30 ml of 0% methanol C under a nitrogen atmosphere over 10 minutes. The solution is allowed to stand for 1 hour, after which 10 ml of water is added, the solution becomes

V Cl

and heat to 20 ° C. The solution is stirred for another 20 minutes, after which the white precipitate formed is deposited. The precipitate is separated by filtration and then taken up in chloroform. Dry the chloroform solution over sodium sulfate. The solvent was removed and the residue triturated with petroleum ether to give 1 g of white crystalline crystals of the product

3030 * 00

THWTA I

E5OUD05

5,8-diazs-1,2-dithia-6-ethoxycarbonyl-3,3,10,10-tetramethylcyclodee-4,8-diene, i.e. Compound 21 of Scheme 9

PE 93-99 ° CIV (thin film) 34-50,

Yield; 53 / ·

174-0, 1650 cm- ¹ ;

C1C1) S 6.9 (m, 2, CH = CN), 3,0-4- 6 (m, 5, -0CH ₂ CH _3, -: H ₂ N-CH), 1.5 Z 15.2 / 0 (1%), -OCH ₂ CH 7.

Technique ix:

To 1.0 g (5 mmol) of the bisaldehyde 68 in 10 ml of methanol is added dropwise. 1.0 g (5 mmol) of the ester 70 and 1 g (12 mmol) of sodium hydrogencarbonate in 20 ml of a 50: 50 by volume mixture of methanol and water were added. The mixture is stirred at rt. 0 ° C for 10 minutes, after which 10 ml of

Water. The resulting mixture is kept at ambient temperature with stirring for 2 hours. Water is added until the resulting white precipitate separates from the solution. The precipitate is separated by filtration and taken up in chloroform.

Removal of the solvent 0.4 g (yield: 21%) of identical REN

in a rotary evaporator, there is obtained Compound 21, which has a PF and one of the product obtained according to

Technique I.

Technique III

Within 2 hours, a solution of 3 g. Of the .alpha.-ester 7 ml of pyridine in 200 ml of methanol is added dropwise. a solution of 8 g of bisaldehyde 66 in 25 ml of methanol. To get

the reaction mixture is cooled in an ice bath after the addition for 1 hour and then allowed to stand at room temperature for 1 hour. The reaction mixture is placed in the freezer (-20 ° C) overnight. The solution is concentrated to a third of

30C00 30S00

WTÀF FX '

In addition,

TRIMTA TlflKTA

[E5OUDO6 i -. SHIELDS i

its volume, water is added and the aqueous solution is extracted with chloroform. The chloroform extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gives a viscous mass, which is dissolved in 20 ml of hexane. The hexane solution is cooled in a puddle / dry ice bath until a white powder separates. The product is collected by filtration and taken up in chloroform. Concentrate the chloroform solution. Crystalline crystals of compound 71 are formed by yielding 7 g of product of 95-95 ° C. The EMH and IV spectra are identical to those reported in the art I.

(Compound E2 of Scheme 9) was prepared according to the procedure described in Example 1,

Technique I.

A solution of 5 g of ester 71 in 20 ml of tetrahydrofuran and 20 ml of aqueous ammonia is stirred at ambient temperature for 2 hours and then left to stand at room temperature for 24 hours. By removing the solvent, a powder is obtained which is filtered off. The product, 6-chloro-5,8-diaza-1,2-dithia-3,3,10,10-tetramethylcyclo-4,3-diene, i.e. Compound 2 of Scheme 9? in a mixture of isopropanol and water. There is thus obtained 4 g (yield:

8b) of product of f. F.lol-10.3Â ° CIV (nBr) 3300; 3180,

1Ó50 cm

-1 1

1 H NMR (CDCl 3) 7.0 (m, 2, -HC = K-), 6.4 (broadband,

2, -COXX), 3,3-4-, 6 :, 77 ^ 3, -CH ₂ -NHC (N) C0 "7 1.5-1.4 Xs, 12) and (qi ₃ ) ₂ 7.

Technique II

Stir at room temperature,

of 5 g of ester 71 in 20 ml of tetrahydrofuran, 20 ml of ethanol and 20 ml of aqueous ammonia solution (28 ml). Removal of the solvent gives Compound E2 as a white powder which crystallizes from toluene as white strips. There is thus obtained 4 g of product of n. F. 193 ~ 194 ° C. TV and MNE spectra identical to those reported in art I.

Example 14: 5-Carbamoyl-5,8-diaza-1,2-dithia-3,3,10,10-tetramethylcyclodecane (Compound 73 of Scheme 9)

To (3) 7 g of amide 72 in 25 ml of 95% ethanol, 2 g of sodium borohydride are added. The mixture is stirred at ambient temperature for 2 hours and then refluxed for 2 hours. The solution is then concentrated in vacuo and added to water to precipitate the product. The white crystalline product is collected by filtration. After recrystallization from a mixture of isopropanol and water, 3 g of 6-carbamoyl-5,8-diaza-1,2-dithia-3, 3,10,10-tetramethylcyclodecane, i.e. Compound 73 of Scheme 9, in the form of white fine needles, of?. ?. 138-139Â ° C. (CDCl3) δ 2.3-4.0 (m, 7-CHN)

2 - 'CH ₂ -C (CH ₃₎ -S-_7) 1.3 (broad band, 2, -C0HH _2), 1.3 /' m, 14, C (CH _{3) 2,} -CHH- CE-J.

Example 15, 5-Aminomethyl-4,7-diaza-2,9-dimethyldecane-2,9-dithiol (Compound 74 of Scheme 9)

A solution of 1.3 g of amide 73 in 50 Bill of anhydrous tetrahydrofuran is added dropwise over 3 minutes.

to a dispersion of 1 g of lithium aluminum hydride in 100 ml of anhydrous tetrahydrofuran. The mixture is then heated at rt. reflux temperature for 20 hours. The reaction mixture is then cooled first and then diluted with saturated sodium potassium tartrate solution. Extract the aqueous phase with chloroform. The combined organic phases are dried over sodium sulfate. The solvent is removed by evaporation in a rotary evaporator, as a viscous oil, 5-aminomethyl-4,7-diazys-2,9-dimethyl-decane-2,9-dithiol, / 4 of Scheme 9.

l, 5 / "m, l4,> C _{(CH3) 2,} -SH.7.

Example 16: 5,8-Diaza-1,2-dithia-3,3,10,10-tetramethylcyclodeca-4,8-diene (Compound 87 of Scheme 11).

1 g of dialdehyde 68, 4.0 g of ethylenediamine are added, with stirring and cooling, over 10 minutes. The resulting slurry is stirred for a further minute, then allowed to stand for 1 hour at room temperature and then cooled for 1 hour in the freezer (-20 ° C). The solid product is collected by filtration and washed with 500 ml of water. The white product obtained is taken up in chloroform and the chloroform solution is dried over sodium sulfate. Removing the chloroform, 2.5 g of 5,8-diaza-1,2-dithia-3,3,10,19-tetPa-methylcyclodeca-4,8-diene, i.e. Compound 87 of Scheme 11 , in the form of a white crystalline product of

r. F. 161-170Â ° C (162-164Â ° C, 163-166Â ° C).

RKN ¹ H (CDC1 ₃₎ i 6.9 (s, 2, -HC = R), 4.2 to 3.0 (doublet of doublet, 2 2 -CH ₂ -CH _2), 1.40 s £ , 6, -C (O H ₃ ) ₂ 7.

Analyze:

30 $ 00

: 30C00

13Z

Calc. for

Found:

52.13 7.88 12.16 27.83 52.20 7.90 12.14 27.7 ^

Example 17: 5,8-Diaza-1,2-dithia-3,3,10,10-tetramethylcyclodecane (Compound 68 of Scheme 11)

A solution of 0.5 g of compound 67 and 0.3 g of sodium borohydride in 23 ml of ethanol is stirred at ambient temperature for 1 hour and then refluxed for 20 minutes. Thereafter, 10 ml of water is added and the mixture is heated for an additional 10 minutes. The solvent is partially removed on a rotary evaporator and the residue is extracted three times with 10 ml portions of chloroform. The chloroform extract is dried over sodium sulfate and the solvent is removed by rotary evaporation. The resulting liquid is cooled by cooling. Flash chromatography (eluent: hexane / dichloromethane / isopropanol a by volume) gives

5,3-diaza-1,2-dithia-3,3,10,10-tetramethylcyclodecane, i.e. Compound 88 of Scheme 11, as a solid product of

* · THE ·

RUN (CTCL ^) 8 3-2 l (m, core 10 protons), l, ll, 2 (s, 6 H _3).

Example 18: NZ- (4,7-Diaza-2,9-dimethoct-2,9-dimethyldecyl-5) -methyl] nicotinamide (Compound 75 8.0 Scheme 9)

Mo course of 1 hour, add dropwise a solution of 9 mmol of the activated ester in 16 l ^ffi 3θ dimethoxyethane 3.4 mmol of the amine £ 4 in 70 ml of dimethoxyethane. A chroma

After 10 minutes, using an oil / acetone / dichloromethane / isopropanol solvent system, 10: 5 (5.1% by volume) indicated that a major component was obtained. The solvent is removed by evaporation and the residue is treated with water. The resulting mixture is extracted with chloroform and dried over sodium sulfate. Removal of the solvent affords the desired product, Compound 75 of Scheme 9.

Example 19: 3- NZ- (4 ', 7'-diaza-2', 9'-dimercapto-2 ', 9'-dimethyldecyl- ¹ ) -methylcarbamoyl-1-methylpyridinium bromide (Compound E6 of Scheme 9)

Compound E2 was reacted with methyl iodide according to the general art described in Example 2b. The desired quaternary salt, ie, Compound E of Scheme 9 is prepared in this manner.

Example 20: Formation of the complex

the general technique described in Example 5 is repeated to convert the other quaternary salts of general formula I into the corresponding radioactive drugs, to convert Compound 76. to Complex 78, Compound δ in Complex 85, etc.

Example 21; 5-Aminomethyl-4,7-diaza-2,9-dimethyldecane-2,9-dithiol

(Compound E4 of Scheme 9)

After 2 hours under an argon atmosphere, 13 g of the amide 72 in 10 ml of tetrahydrofuran hydrochloride are added dropwise to a dispersion of 11 g of lithium aluminum hydride in 300 ml of tetrahydrofuran anhydrous. When the addition is complete, heat

Ioao

1 4

i2.

M

i

I

the reaction mixture was refluxed for 30 hours and then diluted with saturated sodium potassium tartrate solution. It is then treated with 3% hydrochloric acid, then saturated sodium carbonate solution; the filtrate is extracted and the filtrate is extracted with dichloromethane to give an organic solution which is dried over magnesium sulfate. Removal of the solvent gives the desired amine Compound 74 of Scheme 9 as a viscous oil.

A sample of the thus obtained free amine is dissolved in diethyl ether and hydrochloric acid gas is added. A white powder is obtained which is separated by filtration and purified in ethanol / water, thereby isolating the corresponding hydrochloride.

and c and x-. . B·

"Ή iii: (L ₂ '0): Ή '3.3-4 , 2 (m, 9H, HCl 9 "** Ί ί ί ί ί ί ί -, -HC1 -Ug. 12H, C _{(CH3) 2} 7. Analyze: C $ yV H / E 7 Cl, ε; Calc. for Γ v ^c ir-3 pi vc η. 0 to 3 n 'c: 33.63 8.21, 10.69 27.07 16.32 Found: 33.93 7.9% 10.6u 27.05 16.25 Example 22: Color I like 192 of Scheme 24

A mixture of 1 g

amine 74 with 75 ml of acetone and a catalytic amount of

p-toluenesulfonic acid

the solvent is removed by evaporation

with sodium and with aqueous solution

the residue is taken up in chloroform and treated with aqueous solution, saturated with 10% aqueous sodium hydroxide aqueous sodium carbonate and saturated with sodium chloride. The solute is dried over magnesium sulfate and the solvent is removed, yielding 30%

j Λ "ώ * ώ ^Α β; eVouoVs.

viscous mass. Thin layer chromatography (2: 1 chloroform / methanol) indicates the presence of two major components with Rf values of 0.13 ± 0.17 · θ component with the lowest Ff value shows a ninhydrin positive assay , confirming that it is the desired primary amine 192, while the component with the highest Ff value shows a negative reaction:

REK of the HF component C, 73 (ΟΡΟΙ *): Î ± 2.9; 2.5; 1.3-1.5.

the desired aminobenzazolidine amine is obtained in the presence of the desired amine, Compound 192 of Scheme 24.

Example 23: Compounds 191 ® 76 of Scheme 24

Reaction of the primary amine bistiazolidine 192 with the quaternized ester ester 17 or 191 provides the corresponding quaternary bis- benzazolidine, i.e. Compound 193 of Scheme 24,

which may then be removed from the protecting groups, e.g. by reaction with mercuric chloride and further reacting with sulfhydryl acid, to afford the unprotected quaternary compound, Compound No. 6 of Scheme 24.

Example 24: Compound 81 from Scheme 10

In the course of 1 hour, a solution of 7 g (3 mmol) of ester 71 in 50 ml of dry tetrahydrofuran is added dropwise to 1.8 g (47 mmol) of lithium aluminum hydride in

290 ml of anhydrous tetrahydrofuran. The mixture is warmed

16-hour refluxing and potassium and

xo

H

then diluted with a solution of tartar. The organic phase is dried over sodium sulfate

of sodium and the solvent is removed to give a viscous mass of 30%

10

*]

i ·. '

TFliH-TA 3 T TRINTA escudos eJ 'ESCUDOS *

Compound 81 of Scheme 1C. Yield: 65 X.

H FMH (Cl

Cl-): 2.2-2.8; 3.5; 2,3; 1.5Example 25: Compound 53 of Scheme 10

Using the general technique described in Example 22, but substituting an equivalent amount of the alcohol 81, replacing amine 74 gives the bis-benzazolidine alcohol, i.e., the protected opposite portion of Compound 81, Scheme 10. This protected alcohol can then be subjected to the techniques described in detail in Example 23, finally providing the corresponding unprotected quaternary product, Compound 83 of Scheme 10.

Example 26: Compound 32 of Scheme 5

A solution of 17 ml of 2N lithium borohydride in tetrahydrofuran is added to 3θ of anhydrous tetrahydrofuran under an argon atmosphere. In the same solution, 10 g (0.035 mole) of ester 40 in 100 ml of anhydrous tetrahydrofuran is added. The resulting cloudy solution is heated at reflux for 1.5 hours. The reaction is quenched with water and the organic phase is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removing the solvent yields 2 g of the corresponding primary alcohol, Compound 32 of Scheme 5 as a sparge powder which is very soluble in water. Yield; 245-40Â ° C;

1 _H MS · (acetone-d ₆ ): δ 7-6; 4.15; 3.3-4.0.

Example 27: Compound 33 from Scheme 5

To 1 g of the alcohol 32 in 40 ml of anhydrous ethanol is added

3θ οα

a solution of sodium thiobenzoate prepared from 0.1%. g of sodium were 10 ml of ethanol and 1.26 g of thiozozoic acid in 5 ml of ethanol. The reaction mixture is stirred at room temperature for 10 minutes and then warmed to 45 ° C for an additional 10 minutes. The mixture becomes very thick and difficult to stir, separating a yellow product. The product, Compound 35 of Scheme

5, is isolated by filtration and washed with water, whereby 1.2 g of product of? Are obtained. ?. 151-152 ° C.

fr: (faso

dione / scetone-d4):

7, h3)

85-3,1-3,6.

Example 23: Compound '168. of Scheme 1 (

Peune-se 3

κ _c ,

(0.1 mole) of cyanoacetic acid and

11, *

(0.1 mol) of N -hydroxysuccinimide in 150 ml of anhydrous tetrahydrofuran was added dropwise to the cooled suspension. A solution of 20.6 g (0.1 mol) of dicyclohexylamine in 100 ml of dry tetrahydrofuran. The mixture is then cooled to room temperature overnight. Filter to remove the white precipitate which forms and wash with 50 ml of tetrahydrofuran. Concentrate the combined filtrates to give 3 g (yield: _Λ W) of the ester 16) 7. The product

crystallizes from isopropanol as white needles, l. F. 1A-O-12.2 ° C.

A solution of 0.62 g (3.3 mmol) of the ester 1.6 'is added dropwise. in 10 ml of anhydrous dimethoxyethane was added dropwise to a stirred solution of cyclic diamine (0.8 g, 3.3 mmol) in dry dichloromethane (20 ml) at ambient temperature. The solution is stirred for an additional 2 hours and then allowed to stand for 16 hours. Dimethoxyethane is removed by evaporation

30500, 30500

The residue is suspended brown in water to remove

to N-hydroxy-succyrimide. Filters to separate product 168

which, after crystallization from toluene / hexane, provided 0.9 g (yield)

38 ') of fine brown needles, from PF 142-143 C.

1. V. (thin film): 3450, 2250, 1675 cm- ¹ .

ϊΚη (CDCl,):

b 3.7; 2.4-3.6; 3.5; 1,3; 1.25.

Analyze:

Calc. 0 ^ ₃ to ₂₃ ^ Η ^ βθ 2'Found:

51.79 7.69 13.94 21.27 51.99 7.12 14.01 21.34

Example 29: Compound 169 of Scheme 18

A solution of 3 g of the nitrile 168 in 50 ml of anhydrous tetrahydrofuran is added dropwise over 30 minutes to a stirred dispersion of 1.2 g of aluminum hydride and

in 100 ml of anhydrous tetrahydrofuran under an atmosphere of nitrogen. The yellow solution is heated at reflux for 7 hours and then stirred at room temperature for 5 hours. The dispersion is hydrolyzed with saturated sodium potassium tartrate solution, the aqueous phase is extracted with dichloromethane, and the combined organic extracts are dried over sodium sulfate. The rotary evaporation of the solution affords the amine 169 in the form of a yellow viscous oil.

Example 3θ * Compound 170 of Scheme 18

Within 1 hour, a solution of 2 g (9 mmol) of the activated ester 16 in 30 ml of dimethoxyethanol is added dropwise to 2.6 g (8.9 mmol) of amine 16.9 in 7θ ml of dimethoxyethane. One hour later, thin layer chromatography

¹ 30 $, 30S 0;

1, - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

10: 5: 5: 1) indicates the presence of a major component with

Example 31: Compound 40 of Scheme 19

A mixture of 10 g of sodium hydrogen carbonate in 50 ml of water and 200 ml of toluene is added 2 g (0.01 mole) of the ester O, while cooling in an ice bath. 5 g (0.44 mol) of chloroacetyl chloride are added dropwise and the mixture is allowed to warm to room temperature. Extract the organic layer with ethyl acetate, wash with water and brine and then dry the solution over magnesium sulfate. After removal of the solvent, 2 g (yield: 70.1%) of product 40 is obtained as a white mass. P. ?. 85-o7 C.

Example 32: Compound 41 of Scheme 19

A solution of 2 g

(9 mmol) of ester 40 in 20 ml of anhydrous ethanol. To this solution, a further solution of sodium thiobenzoate in anhydrous ethanol (prepared from 0.45 g of sodium in 20 ml of

ethanol

to form sodium ethoxide, which is reacted with 2.5 g

of thiobenzoic acid (A). A precipitation occurs immediately 3θ σσ

; THIRTY ^: ESCLTS

tion. The reaction mixture is heated at reflux for 5 minutes, then diluted with ethyl acetate and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried over magnesium sulfate. After removal of the solvent, 4.1 g of a white powder is obtained. Crystallization from toluene affords 2.4 g of a white product, compound 41, of FF 125-127 ° C (Liter, 129.5 ° C)

(III-C). The spectrum of εΜΠ is in agreement with the structure.

Example 33 Compound 176 of Esomema 19

A mixture of 7.5 g (43 mmol) of iodoethanol, 57 g (43 millimoles) of nicotinamide and 150 ml of acetone is heated at reflux for a period of time. The mixture is cooled and filtered, yielding 1.5 g (yield: 12%) of the product 1/6 of

□ p 7 ° r

1 · «fc · vf SX 9

Example 34: Compound 177 of Scheme 20

To a mixture of 10 g of potassium carbonate in 20 ml of water and 200 ml of toluene is added 5 g (32 mmol) of 3,4-diaminobenzic acid. To the cooled mixture, 14.4 g (127 mmol) of chloroacetyl chloride in 10 ml of toluene is added over the course of one hour. After the addition is complete, the mixture is stirred at room temperature for 30 minutes. Filter to remove the resulting brown product, yielding, after crystallisation from ethanol, 8 g (yield: 82%) of product 1ZZ? of n. j. .

lixem

30:00 a.m. 30:00

· Ί'ίι

(I.e.

14-6

EXAMPLES OF THE INVENTION

I TRJNTA i ESCUOO8

THIRTY

SHIELDS

Example 35: Compound 1/8 of Scheme 20

To 25 ml of ethanol was added 0.17 g of sodium metal and then 1.1 g (7.4 mmol) of thiobenzoic acid. To the resulting brown-yellow solution, 1.16 g (3.7 millimoles) of 177 acid is added. The mixture immediately turns yellow and thick. The mixture is warmed to 200 ml with anhydrous ethanol and refluxed for 2 hours. The filtrate was collected by filtration and crystallized from isopropanol / tetrahydrofuran, yielding 1 g (yield: 53%) of compound 1/8 of r. E. 24-4-24-5C,

Example 36: Compound 1/9 of Scheme 20

500 ml of anhydrous tetrahydrofuran are added. 15.2 g (9.93 mole) of acid l of 3.45 g (3. 03 mole) of N -hydroxysuccinimide. In the resulting suspension, 6 g (0.03 mole) of dicyclohexylcarbodiimide in 50 ml of anhydrous tetrahydrofuran is added over the course of 1 hour. The resulting mixture is stirred at room temperature for 16 hours. The precipitate is removed to remove the white precipitate of dicyclohexylurea which forms and the filtrate is concentrated in vacuo to give a brown product. Flash chromatography of a small sample (eluent: dichloromethane / acetone 3: 1) affords the ester of DEP-11-118 ° C.

Example 37: Compound 183 of Scheme 21

A solution of 10.2 (0.05 mole) of 2-bromoethylsrene brohydrate and 6 g (0.05 mole) of nicotinamide in 150 ml of anhydrous dimethylformamide was heated at 140 ° C for 16 hours. The resulting orecipitate is separated by filtration and washed with ether,

yielding 14 g (yield: 88%) of the title compound

in

147

r. F. 280 ° C (decomp.).

Example 3c: Compound 75 of Scheme 9

A solution of 2 g (7.5 mmole) of amine 74 and 1.65 g (7.5 mmole) of the activated ester .16 in 100 ml of anhydrous dimethoxyethane is stirred at ambient temperature for 24 hours. The solvent is removed by rotary evaporation and the residue is treated with water. The viscous product is extracted with chloroform and dried over magnesium sulfate. Removal of the solvent affords compound 75 as a viscous mass. The EKN spectrum is consistent with the structure. The compound is used without further purification.

Example 39: Compound E6 of Scheme 9

A solution of 0.5 g of amidine 75 and 5 ml of methyl iodide in 20 ml of nitromethane is stirred at ambient temperature for 7 days under argon. After the second day, a precipitate begins to form. This is collected by filtration and treated with acetone to yield 150 mg of the quaternary salt of the? F. 210-215 ° C (decomp.). NMR (DMSO-d6): 0 0.3-9.5;

3.0-η0.0; 1.2-1.5

Example 40: Compound 7.7. of Scheme 9

To a solution of 0.5 g (1 mmol) of the quaternary salt 76 in 10 ml of water, 0.25 g (3 mmol) of sodium hydrogen carbonate and 0.6 g (3 mmol) of dithionite of sodium. The ether (50 ml) is added and the mixture is stirred under nitrogen for 39 minutes while cooling in an ether bath. Extract the aqueous phase with dichloromethane and evaporate to afford 30%

4

t / h L

(I.e.

Thirty> 1 Thirty

SHIELDS · ÇSCUDOS '

The combined organic phases were washed with magnesium sulfate to give the dihydro derivative 77

Example 41: Compounds 81 and 8a of Scheme 10

A solution of 10 g (35 mmol) of ester 71 in 100 ml of anhydrous tetrahydrofuran is added dropwise over 30 minutes while cooling in an ice bath to a dispersion of 4 g (94 millimoles ) of lithium aluminum hydride in 300 ml of anhydrous tetrahydrofuran. The dispersion is then heated under reflux for 24 hours. The reaction is quenched with saturated sodium potassium tartrate solution, then with hydrochloric acid 3η and finally with sodium carbide. The aqueous phase is extracted with chloroform, the combined organic extracts are washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. Removal of the solvent gives the alcohol 81 as a viscous mass. The product is taken up in ether saturated with hydrochloric acid gas, while cooling in an ice bath. There is thus obtained 6 g of salt 81a of 1 ·. ?. 190-191 ° C. The RhN spectrum and the elemental analysis are according to the structure.

Example 42: Compound 10e of Scheme 23

To 24.6 g (0.17 mole) of nicotinic acid and 32 g (0.19 mole) of R-hydroxyphthalimide in 30 ml of tetrahydrofuran is added 2 g of dicyclohexylcarbodiimide in 200 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 24 hours. The white precipitate of dicyclohexylurea is filtered off and filtered. Concentrates

The filtrate and _the qj_ cri _{s t? g} _

only

ss;

149

'30 $ 00 30 $ 00'

lS ^S l: pW! l

lii

, TRINTA; SHIELDS

white solid, twice in ethyl acetate, once in isopropanol and again in ethyl acetate. The various batches of compound 10a thus obtained melt at 132-135Â ° to 1443Â ° C.

Î'(trci): 08.1 (-9.5 (1, 3H, Î'H), 7.95 (s, te, Ar- H), 7.5-7,

Example 43: Compound 1% 1 of Scheme 2.3

A solution solution is introduced into a pressure- (16.6 millimoles) of ester I90, and 6 g (42.4 mmol)

of methyl iodide in 40 ml of acetone and heated in an oil bath (bath temperature: 6øC) for 12 hours. It is then filtered, yielding 4.5 g (yield: 59%) of the quaternized sugar ester 11.1. The product darkens to l0 ° and melts

at 5øC.

¹ H PM '(mo-d ₆ ): δ 8.2-9.9 (m, 4H, Py-H) · 6.1 (s, 4h, Ar-H); 4.52 (s, 3H, M-CH ₃ ).

Example 44: Compound 180 from Scheme 21

To 9 g (14.9 mmol) of the activated ester in 100 ml of dimethoxyethane is added 0.916 g (15 mmol) of ethanolamine

in 50 ml of dimethoxyethane. The reaction mixture is stirred at room temperature for 43 hours; then filtered to remove the white precipitate which forms. Concentrating the filtrate gives another 2 g of the product. Total isolated amount: 4 g (yield: 49%) of compound 130, mp 205-210 ° C.

^J H NMR (DE £ od): 7.5-10 S; 4,3; 3.3-3.75 3.3 ·

Exem120

Example 45: Compound 1 of Scheme 25

30 $ 00

t-

ESCUSOS,

8 g of the 1Î ± acid and 1.8 g of Î ± -hydroxysuccinimide are dissolved in 200 ml of tetrahydrofuran. To this suspension, 3.16 g of dicyclohexylcarbodiimide are added in 25 ml

of tetrahydrofuran. The mixture is then stirred at room temperature for 16 hours. Filter to remove the white precipitate which forms and concentrate the filtrate in vacuo. The product, the activated ester 179 is crystallized from toluene.

Example 46: Compound 194 of Scheme 25

To a solution of 0.14 g (8 mmol) of ammonia in 150 ml of dimethoxymethane is added a solution of the activated ester (4.7 g, 6 mmol). The reaction mixture is stirred at room temperature for 16 hours. The solution is concentrated in vacuo to give 3 g of the amide 194 as a white product.

Example 47: Compound E of Scheme 23

To 6.12 g (23 mmol) of the amine 4 in 100 ml of anhydrous dimethylformamide is added dropwise over 4 hours 2.2 g (6 mmol) of the activated ester 1e in 1 ml of The reaction is stirred at -47 ° C (acetonitrile / carbonic snow) under argon. The reaction is stirred for 2 hours at -47 ° C and then allowed to stand at A freezer was added in vacuo to the reaction mixture at -20 DEG C. overnight The dimethylformamide was removed in vacuo and the residue was added to the residue of xylene and the solvent was removed again in vacuo. The residue is dissolved in benzene (75 ml) and triturated with petroleum ether, whereupon a gummy product is separated.

151

«.A * ¹

-y;

, -TftfKTA l SI Thirty

What are you doing? SHIELDS ^

the resulting gummy residue is suspended in the same solvent. High pressure liquid chromatography indicates the presence of a major maximum with some amine. A flash chromatography (eluent: methanol) of a small sample of the reaction mixture yields a product which the high pressure liquid chromatography shows to consist of the amine. residual and the desired quaternary salt 76.

Example 48: Compound 76 of Scheme 23

0.5 g (1.4 mmol) of the 1α-1 quaternary compound are dissolved in 20 ml of dimethylformamide. The reaction is carried out at -47 ° C for 2 hours under an argon atmosphere. The solvent is removed in vacuo and the residue is treated five times with benzene / petroleum ether. High pressure liquid chromatography results indicate that most of the amines were removed, leaving the desired quaternary salt 26.

Example 49: 1-Methyl-3-2-

(Compound 22.2 of Scheme 32) and the title compound as a white solid (0.8 g) as a pale yellow solid. 1H NMR (DMSO-d6):?

To a gentle reflux, 100 mg (0.23 mol) of amino hydride monohydrochloride monohydrate in 15 ml of anhydrous pyridine is heated to reflux with 200 mg (0.438 mmol) of the quaternized activated ester 191. After 2 hours, mix with OTS and place the mixture aside to cool. The volatiles are removed in vacuo, the residue is washed with 10 ml of water and the residue is taken up in chloroform. The layer

152

with 20 ml of chloroform, the extracts are combined, the organic layers are dried over magnesium sulfate and evaporated to dryness to give an orange oil. The oil is taken up in a minimum of hot ethanol. The trituration resulted in the precipitation of 75 mg (yield: 51%) of the quaternary salt 222 as a pale yellow powder, mp 214-216 ° C.

IR (KBr) 3000-3600, 1670, 1535, 1470 cm-

-1

• 'H NMR (DKS0-d _6): δ 9.5i 8.1-9A; 7 _; , 1-7.6; M-, 5; 2 , 3-3.8. Analyze: the Calc. for ( ^: 22 ^H 29 ^B 8 ^{IO S -1 / 2H} 2 ^0: if2.51 Z, a6 18.01 10.31 Found: * t 2.70 77 17.7% 10.42

Example 50:

4 '- [[1- (1''''-1''', 4 '' -dihydropyridine

(4-methylthio-semicarbazone), hydrated with 44 mol of E2 O (Compound 223 of Scheme 32) was dissolved in dichloromethane

104 mg (0.17 mmol) of the quaternary salt 222 in 30 ml of water, which was cooled with ice, was treated with 140 mg (1.7 mmol) of sodium bicarbonate and 30 mg (1, 7 mmol) of sodium dithionite. Ethyl acetate (50 ml) is added to the stirred solution and nitrogen gas is bubbled (where oxygen has been removed by passing through an alkaline solution of pyrogallol) through the reaction mixture. After 45 minutes, the organic and aqueous layers were separated and the aqueous layer was further extracted with 3 ml of ethyl acetate. Dry the organic layers over magnesium sulfate and reduce the volume of

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Iia

_z : HWAs

solvent by evaporation in vacuo. The product is eluted through a short column of neutral alumina (Aldrich, 150 mesh, Brockman 1). After evaporation of the solvent, 57 mg (yield: 70%) of the dihydro derivative 223 is obtained as a yellow solid. The product darkens to 130 ° C and decomposes at 185 ° C.

^X H NMR (CDCl? / DMSO-d ^): b 8.0-8.3; 7.1-7.5; 6.95; 6.0-6.4; 5.6-5.8; 4.5 - β, β1-3,7; 3.2 <2.8-3.4; 2,3.

Analyze:

W % H % N% s % Calc. for Ο ^ Η ^ θΝθΟβ ^ V + H ₂ Q: 53.80 6.41 22.82 13.04 Found: 53.80 6.27 22.63 13.02.

The Reaction Schemes and previous examples illustrate the preparation of a wide variety of derivatives according to the present invention wherein the redox dihydropyridine-pyridinium salt portion of the vehicle may be one of the groups [

As described above in sheets 19 to 43, wherein p is zero. The preparation of other derivatives of this type will become readily apparent to those skilled in the art from the teachings mentioned above, in particular with regard to the illustrative synthetic processes detailed in the PCT patent application mentioned above, i.e. PCT In addition, it is possible to adapt the processes of PCT / US83 / 00725 and the present specification to the preparation of the derivatives bearing the vehicle portions described on pages 19 to 43, wherein p is the integer 1 or 2.

Some illustrative processes for the preparation of the compounds according to the present invention are described below.

wherein the carrier comprises a group of general formula,

0

integer 1 or 2.

It should be noted that, in the same way as the derivatives in which p is 1 or 2 can be prepared by processes analogous to those described in the reaction schemes for the derivatives in which p is zero, also derivatives in which the symbol p represents zero can be prepared by processes analogous to those described below for the derivatives in which p is 1 or 2. The processes described below must, of course, be adapted to the specific chelating agent chosen for the formation of derivatives in a manner analogous to that of the reaction schemes mentioned above.

Illustrative synthesis processes

I. Processes for preparing derivatives of the groups

-NH ₂ or -NH Process A

The chelating agent or its protected duplicate (eg compound 74 in Scheme 9 or compound 192 in scheme 24 or compound 221 in Scheme 32) is reacted with nicotinuric acid chloride, nicotinuric acid anhydride or nicotinuric acid , in the presence of an appropriate coupling agent such as di cyclohexylcarbodiimide, in an appropriate organic solvent, to give the glycinnicotinamide or nicotinuramide

correspondents. The nicotinuramide is then quaternized, typically by reaction with methyl iodide in a solvent

organic phase to give the quaternary derivative which is then deprotected if necessary and reduced by reaction with sodium dithionite or sodium borohydride in the opposite manner. described above in general.

Alternatively, the glycine may be reacted first with a reagent capable of introducing an amino protecting group such as benzyloxycarbonyl or tert-butoxycarbonyl and then reacting the N-protected glycine with the chelating agent or its duplicate protected in the presence of a linker with dicyclohexylcarbodiimide, thereafter removing the protective group from the nitrogen atom and then reacting with nicotinoyl chloride or nicotinic anhydride or with nicotinic acid in the presence of dicyclohexylcarbodiimide or another binding agent to give the nicotinuramide. The nicotinuramide may then be quaternized, the quaternary compound deprotected if necessary and reduced in the manner described in the previous paragraph.

can repeat the technique of the second paragraph of this pro

by using picolinic acid or its acid chloride or anhydride or isonicotinic acid or its chloride or anhydride instead of nicotinic acid or its chloride or anhydride respectively to convert chelating agents or their protected glycyl- picolinamides and glycyl-isonicotinamines and then into the corresponding quaternary and dihydro derivatives. The technique described in the first paragraph of this case may also be adapted.

Moreover, any of these techniques can be repeated,

156

substituting glycine or nicotinuric acid therein for a different amino acid or nicotinic acid derivative thereof, e.g. substituting glycine for alanine, valine, leuine, phenylalanine, isoleucine, methionine, asparagine or glutamine

Alternatively, the chelating agent or its protected duplicate may be reacted with an activated ester of nicotinuric acid or the like, e.g. a succinimidyl ester, such as the compound of formula

0 '

quaternize the resulting product, unprotected if necessary, and reduce in the manner described in the first paragraph of this process to obtain the identical products. As yet another extremely advantageous alternative, the activated ester, e.g. the above succinimidyl ester may be quaternized (eg by reaction with methyl iodide) then reacting the quaternized activated ester with the drug. The quaternary compound thus obtained may then be deprotected, if necessary, and reduced in the manner described in the first paragraph of this pro

ces.

Process B

This process is especially used when the -NH- group is part of an amide or imide or a very low primary or secondary amine.

the chelating agent is first reacted (e.g.

compound 52 in Scheme 7) with an aldehyde e.g. formaldehyde, benzaldehyde, acetaldehyde or chloral (CKCCHO) for example in the case of formaldehyde, the -NH- group is converted into a

CH 2 OH, whereby an appropriate group forms

-No bridge. The resulting compound is then reacted with nicotinuric acid in the presence of an appropriate dehydrating agent, or with nicotinuric acid chloride or nicotinuric acid anhydride, to give the corresponding nicotinuric acid ester of partial formula

The resulting intermediate compound is quaternized and reduced thereafter as described in Process A. The alternative technique, which utilizes an activated ester or a quaternary derivative thereof and which is described in Process A may also be used to advantage here.

As an alternative, the stages subsequent to the formation of

CH-OH group I

May be replaced by steps similar to those detailed in the second paragraph of

The technique of the previous paragraph may be repeated using picolinic acid or its acid chloride or anhydride or isonicotinic acid or its acid chloride or anhydride instead of nicotinic acid or its acid chloride or anhydride respectively ( as recited in the second paragraph of Process A), to convert chelating agents to glycyl-picolinic acid esters and corresponding glycyl-isonicotinic acid esters.

158

and then into the corresponding compounds according to the

with the present invention. Likewise, amino acid derivatives other than glycine may be prepared. See Case A, last paragraph.

Still, as another alternative, one may react,

with thionyl chloride, the intermediate compound containing the C H 2 OH group or the like to give the corresponding compound

which includes a CBâ, "Cl group or a similar group. You can then

The said derivative is reacted with a metal salt (in particular a silver salt or a talous salt) of nicotinuric acid or the like (formed, for example by reaction of nicotinuric acid or the like with fresh silver oxide or hydroxide or with ethoxide ethoxide). The resulting nicotinuric acid ester of partial formula,

or a similar derivative is then quaternized and then reduced in the manner described in Process A.

Process C

The technique described in the second paragraph of Process A is used except that after removing the protecting group from the nitrogen atom the deprotected product is reacted with 3-quinoline carboxylic acid or its acid chloride or anhydride instead nicotinic acid or its acid chloride or

acid.

The technique described in the first paragraph of Process A may also be adapted to the production of 3-quinolinecarboxylic acid derivatives. In addition, Process C may be associated with Process A to provide the 3-quinolinecarboxylic acid derivatives of the chelating agent type used in the process.

The technique described in the first paragraph of this process can be repeated using 4-isoquinolicarboxylic acid or its acid chloride or anhydride to convert the like agents mentioned with Processes A and B into the corresponding 4-isoquinolinecarboxylic acid derivatives.

The technique described in the first or third paragraph of this process may be repeated by replacing the glycine used in the first step with a different amino acid, e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine (See Process A, second paragraph).

The general techniques described above may be used to prepare the 1,2-dihydro derivatives and also the 1,4-dihydro derivatives.

Process D

The technique described in the second paragraph of Process A is used, but using a reagent of formula

cooh ₂ cooh

instead of nicotinic acid. (That starting compound may be prepared by reaction of nicotinic anhydride,

160

^: The '· r

ft

Bifei? '' ³ '' ét '* ¹ a5SÍ

j 'Ãc-UpPS | prAiA

nicotinoyl or nicotinic acid with glycolic acid).

The prior art may be repeated using pi acid

colinic acid or its acid chloride or anhydride or isonicotinic acid or its acid chloride or anhydride instead of nicotinic acid or its acid chloride or anhydride respectively in the preparation of the above-mentioned reagent. This variation allows to obtain a reagent of formula,

/ ^N s, C00CH ₂ C00H

0

V

or

₂ C00H -C00CH

which can then be used in place of nicotinic acid to prepare chelating agent derivatives or their protected duplicates as those mentioned in Process A.

Process Ξ

The technique described in the second paragraph of Process A is used, but substituting nicotinic acid with a reagent of formula

Zy ^c ®2

O

V

I.

(CH _{2) n} C oo ^H

in which n represents an integer from 1 to 3, preferably 2.

(This reagent may be prepared from nicotinamide, e.g.

ex. when n is 2, by reacting 3-isopropionic acid with nicotinamide). It can then be eliminated

30 $ 00

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AclVoa I {. Acupog |

the protecting groups of the quaternary compound thus obtained, if necessary and reducing the deprotected compound in the manner described in Process A. See also Scheme 26.

The technique described above may be repeated using pyraninamide or isonicotinamide instead of nicotinamide in the preparation of the above-mentioned reagent. This variation allows a reagent of formula

CONH,

or

CONH,

O

(CH _{2) n} C00H

(CH-) COOH n

which can then be used, instead of nicotinic acid, in the art described in the first paragraph of this process,

II.

Processes for the preparation of derivatives of -OH groups

Process F

The chelating agent or its protected duplicate (eg compound 81 of Scheme 10 or the corresponding bisistizoline) is reacted with nicotinuric acid chloride, nicotinuric acid anhydride or nicotinuric acid in the presence of a coupling agent such as dicyclohexylcarbodiimide, in an appropriate organic solvent to provide the corresponding glycylnicotinate or nicotinurate. The nicotinurate is then quaternized, the protecting groups are removed, if necessary, and then reduced in the manner described above in Process A. The alternative technique using a ester or a quaternary derivative thereof and which is described in Process A.

Alternatively, the glycine may be reacted first with a reagent capable of introducing an amino protecting group such as benzyloxycarbonyl or butyl tert-carbonyl, and then reacting the N-protected glycine with the chelating agent or the its protected duplicate in the presence of a coupling agent such as dicyclohexylcarbodiimide, removing the protective group from the nitrogen atom and then reacting the deprotected product with nicotinoyl chloride or nicotinic anhydride, or with nicotinic acid in the presence of dicyclohexylcarbodiimide or another agent to give the nicotinurate. The nicotinurate may then be quaternized, eliminating the protecting groups if necessary, and reducing the quaternary compound in the manner described in the preceding paragraph.

The technique described in the second paragraph of this process may be repeated using picolinic acid or its acid chloride or anhydride or isonicotinic acid or its acid chloride or anhydride instead of nicotinic acid or its chloride or respectively, to convert the chelating agents to the corresponding glycyl-picolinic acid esters or the corresponding glycyl-isonicotinic acid esters and then to the corresponding compounds according to the invention, the technique of the first paragraph of this process. In addition, any of these techniques may be repeated by subjecting the glycine or nicotinuric acid used above to a different amino acid or a nicotinic acid derivative thereof, e.g. substituting glycine for alanine, valine, leucines, phenylalanine, isoleucine, methionine, asparagine or glutamine.

Process G

The technique described in the second paragraph of Process F is used, but substituting a reagent of general formula for nicotinic acid,

(CH _{2) n} C00H

in which n is an integer from 1 to 3, preferably 2,

(prepared in the manner described in Process E). You can then

the protecting groups of the resulting quaternary salt are removed, if necessary, and reducing the deprotected product in the manner described in Process A.

Process G is used in particular in the preparation of chelating agent derivatives in which the hydroxy group is hindered.

Alternatively, Process G may utilize the technique described in the second paragraph of Process F, but using a reagent of general formula

conh ₂

or ¹

COOH ₂

I or

(CH) n COOH 2

(CH _{2) n} C00H

(prepared by the method described in Process E) instead of

ι64 ·

of nicotinic acid.

Techniques of this process may be repeated by substituting a different amino acid for the glycine used in the first step, e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine. (See Case A, second paragraph).

Process H

The procedure described in Process F, according to the paragraph, is used except that, after the removal of the protecting group from the nitrogen atom, the deprotected compound is reacted with 3-quinolinecarboxylic acid or its acid chloride or anhydride instead of nicotinic acid or its acid chloride or anhydride.

The technique described in the first paragraph of Process F may also be adapted to the production of 3-quinolinecarboxylic acid derivatives.

The procedure of Method H can be repeated using 4-isoquinolinecarboxylic acid or its acid chloride or anhydride instead of 3-quinolinecarboxylic acid or its acid chloride or anhydride.

Nicotinic acid or its acid chloride in Procedure B, fourth paragraph, may also be substituted for 3-quinolinecarboxylic acid or its acid chloride or anhydride or 4-isoquinolinecarboxylic acid or its acid chloride or anhydride to give to obtain the corresponding derivatives.

The general techniques described above can be used to

prepare the 1,2-dihydro derivatives and also derivatives thereof

1,4-dihydro.

Process I

The technique described in the second paragraph of Process F is used, but substituting nicotinic acid for a reagent of formula,

C00H C00CH ₂

The nicotinic acid in Process B, paragraph 4, may also be substituted for the initial compound mentioned immediately above to provide the corresponding derivatives.

Alternatively, Process I may be carried out according to Process F, second paragraph, except that a reagent of formula

ZX) QCH ₂ COOH

ο I

V

or

-C00CH _or C00H

tz

(prepared in the manner described in Process D). The nicotinic acid in Procedure B, fourth paragraph, may be substituted for the starting alternative compounds of Process I to provide the corresponding derivatives.

The first or third particle technique of this process can be repeated by replacing the glycine used in the first phase with a different amino acid, e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine. (See i-process A, second paragraph).

166

III.

A process for the preparation of derivatives of the group -C00H

Process J

Nicotinuric acid (N-nicotinoylglycine) or an activated ester thereof is reacted with an aminoalkanol of general formula

H ₂ R = 2 '-OH

in which 2 'represents a straight or branched chain C -C-C alquil alkylene group,

for example. 2-aminoethanol, to yield the corresponding intermediate alcohol, for example in the case of 2-aminoethanol, an intermediate of formula,

0 0

11 II

-CNHCH ₂ CNHCH ₂ CH ₂ 0H

This alcohol is then reacted with a chelating agent which bears one or more carboxyl groups in the presence of an appropriate coupling agent such as dicyclohexylcarbodiimide.

The compound thus obtained is then quaternized and then reduced in the manner described in Process A.

Nicotinuric acid can be obtained commercially. However, it may be readily prepared and further starting compounds thereof, by reacting the chosen amino acid with the acid chloride, nicotinic acid, picolinic acid, triisic acid, 3-quinolinecarboxylic acid, 4 -isoquinolinecarboxylic acid or the like to provide the desired N-substituted amino acid which can then be reacted with an aminoalkanol in the manner described above.

167

Process L

The chelating agent is first reacted with ethylene glycol (or other dihydroxyalkanol having up to 8 carbon atoms) in the presence of a suitable coupling agent such as cyclohexylcarbodiimide to convert the group (s) -COOH in the group of formula,

-COOChb _0-CH z OH cl

0

II

I or in other group (s) of formula -CO-Z'-OH

An N-protected amino acid, such as D-benzyloxycarbonylglycine, is then reacted with it, which was prepared in the manner described in Process A, in the presence of dicyclohexylcarbodiimide or another suitable coupling agent. Removing the protecting group, eg. by catalytic hydrogenation, a derivative of the chelating agent is obtained in which the original -COOH group (s), if ethylene glycol and glycine were used, were converted into the group

0

II

) -cooch ₂ ch ₂ occh ₂ nh ₂

The intermediate is then reacted with a compound of formula

/ Y ^ CONH, O

CH ₂ CH ₂ C00H

or the like prepared in the manner described in Process E in the presence of a coupling agent such as dicyclohexylcarbodiimide to give the desired quaternary derivative. The reduction subse168

to provide the corresponding dihydro derivative is carried out in the manner described in Process A.

The above-described technique can be repeated using a reagent of the formula,

CONH,

X \ o

COOH ₂

CH ₂ CH ₂ C00H

O

w

or

CH = CH _or CHH á to d

or the like, of the compound

prepared by the method described in Method B intermediate of formula,

instead

ch ₂ ch ₂ cooh

Process M

A chelating agent bearing a -COOH group with an equivalent amount of inositol is reacted with

the presence of dicyclohexylcarbodiimide or other suitable coupling agent to convert the -COOH group to a group of formula,

By reacting that intermediate with nicotinuric acid, in the presence of a suitable coupling agent, or with

an activated ester of nicotinuric acid, an intermediate is prepared in which the -COOH group is converted into a group of general formula

in which each or a group

R 2 represents a hydrogen atom

-cch ₂ hhc

varying the number of original hydroxy groups esterified with the amount of nicotinuric acid used.

Subsequent quaternization and reduction are effected in the manner described in Process A.

Alternatively, the prior art may be repeated by replacing the nicotinuric acid with an analogous starting compound, prepared by reacting the chosen amino acid with the

nicotinic acid, picolinic acid, isonicotinic acid, 3-quinolinecarboxylic acid, 4-isoquinolinecarboxylic acid or the like.

By repeating the technique described in the first paragraph of this process and using a larger amount of the chelating agent (eg 2 to 5 more moles per mole of inositol), an intermediate compound containing from 2 to 5 elder residues is obtained and from 4 to 1 hydroxy groups. This intermediate is then reacted with nicotinuric acid to convert at least one hydroxy group to the group of formula,

0.

1Ζ0

The subsequent quaternization and reduction is effected in the manner described in Process A.

Process N

The chelating agent is first reacted with 1,2-propylene glycol (or other dihydroxyalkanol containing up to 8 carbon atoms) in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide to convert the group (s) ) -COOH group in the group (s) -C00 CH-CHOH (or other group of formula

(Ζ-Ζ'-ΟΗ). The resulting intermediate is then reacted with nicotinuric acid in the presence of a suitable coupling agent or with an activated ester of nicotinuric acid to provide an intermediate of partial formula

-C? CH?

ch ₃

Succinct quaternization and reduction are carried out in the manner described in Process A.

Alternatively, the prior art may be repeated by substituting nicotinuric acid for an initial analogue compound prepared by reacting the chosen amino acid with the nicotinic acid acid chloride, picolinic acid, isonicotinic acid, 3-quinolinecarboxylic acid, 4-isoquinolinecarboxylic acid or the like.

171

Glucosamine of formula

with nicotinuric acid, using equimolar amounts of the reactants, in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, or with an activated tinnitrile acid ester. The resulting intermediate of formula

with a chelating agent having a reactive -COOH group in the presence of dicyclohexylcarbodiimide or another suitable coupling agent, substituting one or more of the hydroxy groups for acid residue (s), the number of groups substituted with the quantities of reagents used.

Alternatively, you may repeat the prior art, replacing nicotinuric acid with an analogous starting material, prepared by reacting the amino acid selected with the chloride of nicotinic acid acid, pieolínico acid, isonicotinic acid, 3- ~ q ^u yolinecarboxylic acid, 4-isoquinoline

172

carboxylic acid or the like.

Appropriate non-toxic diluents or carriers,

Pharmaceutical compositions for use with complex esters of general formula III will become apparent to those skilled in the art. See, for example, "Remington's Pharmaceutical Sciences ^1"

4 ^ª Edition (1970). It is clear that the choice of diluents or vehicles

will depend on the exact nature of the particular chosen dosage form.

The dosage ranges for administration of the complexes according to the present invention may vary with the size and type of patient, for the purpose for which the complex was administered, with the dosage form envisaged, and the like, as will be referred to below . The amount of dosage form determined necessary to provide the desired dose of the radioactive drug depends, of course, on the concentration of the complex in any of its pharmaceutical compositions / dosage forms and their activity.

By way of example only, a dose of 4850 mg / kg of a radioactive drug of formula III, injected into the tail vein or rat carotid vein, required for the "retention" mechanism, will present a very significant difference between levels of radioactivity in the brain and periphery, with the consequent easy radiography of the brain; the radiograph at the end of the cervix at 60 to 9θ minutes after administration will be more effective, since it takes advantage of this brain / periphery differential.

The present radioactive drugs are generally administered intravenously. Administration of delayed release, typically by slow intravenous infusion, will further enhance the site specificity of the present redox system.

the release rate of the radioactive drug of formula III from the delayed release system should be comparable to the in vivo oxidation rate of the dihydro form of formula III to give the quaternary form IV, for the purpose the highest degree of specificity increase.

In another embodiment, the present invention also provides a process for the preparation of a diagnostic agent for visualization of an organ such as the brain. To this end, the form penetrates through the blood-brain barrier of general formula III is mixed with an aqueous buffer solution medium having a pH of from about 4 to about 8, preferably from about 6 , 5 to about 7.5, in an amount effective to form a radiograph.

The preparation of the radioactive drug may be carried out in the hospital or in a similar location where the patient is in order to minimize the radioactivity losses caused by the weakening of the radioactive metal. Considering that the preparation for visualization is injectable, it should be sterile and pyrogen-free; it should preferably also be isotonic. To this end, a so-called marking kit can be provided which allows a simple, fast and safe labeling of the solution to be injected with the radioactive metal, e.g. p. These kits are especially advantageous when using a short-lived radioisotope as technetium-99-m.

The kit consists of a glass collection vial which receives and / or contains an aqueous medium in which the complexation reaction can be carried out. Further, the kit comprises

the chelating agent of formula II or the agonist precursor

PURPOSE,

Y ''. '-'--V: - _{Λ Λ,} ··.

Bcl®® Snj

• Tet *? * *

_EWtí0Cr5_

the chelating agent of formula I is a pharmaceutically acceptable reducing agent to reduce the radioactive element to an oxidation state which is suitable for the formation of a complex with the chelating agent (and also for reducing the niridinium bromide to the corresponding dihydropyridine form when a chelating agent precursor of formula (1) is present.

In the case of technetium-99m, the radioactive element is received from a radioactive isotope generator under the. aqueous solution of pertechnetate (TcOâ, ") as a liquid eluted in isotonic saline, as is well known for the purpose, the amount of Tc-99m required to produce sufficient amount of radioactive drug of formula III for diagnostic purposes is generally comprised between 0.01 milliOurie (mCi) and about 500 mCi per ml of 99m-pertechnetate solution. The reducing agent for pertechnetate may know one

thiosulfate or a dithionite if the reduction reaction is carried out in an alkaline medium or a tin (II) salt such as stannous chloride if the reduction reaction is carried out in acidic medium.

A kit for the preparation of an injectable radioactive drug, eg for forming a complex of a radioactive metal-labeled organ specific agent, comprises, in separate containers: (1) a sterile, biologically compatible aqueous medium suitable for the formation of a complex with a radioactive metal, (2) a complexing agent containing a dihydropyridine pyridinium salt vehicle of Formula I

or II, with that compatible, and (3) a pharmaceutically acceptable reducing agent for the radioactive metal.

The dihydryridine vehicle standard <---------- pyri-

may be present in the kit, as desired, either. in its oxidized state or in its reduced state. The reducing agent for the radioactive metal may be chosen so as to also reduce the portion of the oxidized carrier, if present, since the radioactive metal is reduced to form the complex preparatory for injection of the radioactive drug into a test animal or in a patient. In a preferred embodiment of the present invention, a reducing agent capable of reducing both the oxidized form of the carrier moiety and the radioactive metal and the chelating agent precursor is present in the kit. In an especially preferred embodiment, the kit comprises, in separate containers (preferably hermetically sealed glass vials having a capacity of about 5 ^to 25 ml), (1) a sterile, biologically compatible aqueous medium ( 2) a chelating agent precursor of Formula I and (3) a pharmacologically acceptable reducing agent capable of reducing the chelating agent precursor of Formula I to provide a chelating agent of Formula II and also capable of reducing the radioactive metal to an oxidation state where it can form a complex with the chelating agent. of formula II to obtain a radioactive drug of formula III. It is preferred that the reducing agent is the sodium dithionite; it is also advantageous if the radioactive metal is technetium. It is preferred to carry out reduction with dithionite in alkaline medium; this may be achieved by ensuring that the above-mentioned aqueous medium (1) has an alkaline pH, or by adding an appropriate base (eg sodium hydroxide, sodium carbonate) when the components of the kit and the pertechnetate solution . Still, as another alternative, the case may

ender only two separate components: (1) the biologically compatible, essentially neutral sterile aquosn medium containing the chelating agent precursor of Formula I; and (2) the reducing agent and the base, e.g. sodium dithionite and sodium carbonate.

Radioactive metal ions are generally not supplied with the kit because of the relatively short half-lives of the radioactive isotopes commonly used. In contrast, the radioactive isotope is provided separately as described above and admixed with the components of the kit shortly before use, as is known for other radioactive drug delivery systems. In the case of technetium-99m, the pertechnetate solution and the alkaline aqueous medium may first be pooled and then heated, at 40-95 ° C for 10-20 minutes in the presence of the reducing agent, then cooling to or below the ambient temperature prior to the addition of the precursor

In another case, the technetium will be reduced prior to the reduction of the quaternary portion to the corresponding dihydro form if this is where a substantial portion of the quaternary salt of formula I is likely to be complexed with reduced technetium to forming the quaternary complex of formula 17 in the reaction mixture as an inert compound to give the dihydro complex of formula III, instead of the quaternary salt of Formula I being first converted to the chelating agent of general formula II and then into the dihydro complex of formula III. Alternatively, if very little heat or no heating, the precursor may be present in the initial mixture prepared from the kit, and is

also in this case the quaternary salt of formula I will first be reduced to dihydro compound of formula II, which will then complex with the reduced technetium to form the complex of formula III. If the mixture is moderately alkaline, e.g. with a pH comprised between 8 and 9, it may be administered as is after reduction and chelation has occurred to form the radioactive drug of formula III, or the pH may be adjusted to about 7. If the mixture is more strongly alkaline, e.g. of pH 13, it will generally be more advantageous to adjust the pH to a slightly alkaline or neutral value.

Whatever the exact configuration of the kit, it is preferred that it contains an excess of chelating agent precursor I or chelating agent II with respect to the radioactive isotope to which it is to form a complex, for example a common excess of 1: 2. The reducing agent is present in a large excess relative to the precursor of the chelating agent I, e.g.

1: 5 ^to 1! 1θ When the chelating agent of formula II is present in place of the precursor of formula I, it is preferred that the reducing agent is present at a slight excess relative to the radioactive isotope.

For visualization, the diagnostic agent is administered to a patient, generally intravenously, with or without further dilution with a carrier such as saline, phosphate buffered saline, plasma or the like. In general, the unit dose to be administered has a radioactivity of about 0.01 milliCurie (mCi) to about 100 milliCuries, preferably about 1 mCi to about 20 mCi. The solution to be injected into an adult patient per unit dosage is from about 0.01 ml to about 1 ml.

After intravenous administration, can be carried out radiography organ ^{r in} vivo "after a few minutes. Eventually, radiography can also be made a few hours after injection, depending on the radioactive material half-life that has been introduced in the patient and the amount of this introduced material. It is preferable to perform the radiography 60 to 90 minutes after intravenous administration.

Any conventional method of radiography may be used for diagnostic purposes when performing the present invention.

In summary, in its more embodiments, the present invention can be seen in that it provides compositions containing; (1) the remainder of a chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxy, hydroxy, amide and imide, said functional group not being essential for the chelating properties of said chelating agent and said moiety being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups, said chelating agent being either (a) capable of forming a complex with a radioactive isotope of metal or (b) complexed with a radioactive isotope metallic; and (2) a portion of dihydropyridine redox vehicle

Pyridinium salt; the said carrier agent moiety being bound together.

^ 11 ^ 1 ¹ 1111 l ll || - / '-J

chelating and said carrier portion to one another to form a hydropolitically decomposable bond.

While the invention has been described in terms of various preferred embodiments, one of ordinary skill in the art will appreciate that various modifications, substitutions, omissions and alterations can be made without departing from his spirite.

Therefore,

IZ2

The scope of the present invention is intended to be

solely limited by the scope of the following claims

Claims (1)

Claims 16 Ο 1. A process for the preparation of salts of general formula £ QC ⁺ 7 _and mX ^_n of said chelating agent at least one amino, carboxyl, hydroxy, amide or imide functional group, said functional group not being essential for the complexing properties of said chelating agent, said remainder being characterized by the absence of an atom of hydrogen in at least one of said reactive functional groups of the chelating agent; y represents the integer 1 or 2; ⁷ represents the hydrophilic ionic pyridinium salt form of a dihydropyridine-pyridinium salt (vehicle) redox system; X represents the anion of a pharmaceutically acceptable organic or inorganic acid, n represents the valence of the acid anion, and n represents a number which, when multiplied by n, is equal to y, characterized in that - reacting a chelating agent or a protected derivative thereof comprising at least one reactive functional group selected from the group consisting of amino, carboxy, hydroxy, amide and imide, said functional group being not essential for the purposes of the invention .es complexing of said chelating agent with a reagen you can replace a hydrogen atom of at least one of said reactive functional groups by a radical.Z QC ⁺ _ /, or 181 a radical capable of being quaternized to provide a radical quaternized thereafter, when said hydrogen atom has been replaced by a radical capable of providing a radical when the said protected derivative is used as the starting compound, the protecting group (s) is removed to give the corresponding salt of formula I. 2. A process according to claim 1 for the preparation of salts of general formula I in which the said moiety of a chelation agent is characterized by the absence of a hydrogen atom in at least one amino or hydroxy reactive functional group of the chelating agent, characterized in that correspondingly substituted starting compounds are used. 3. A process according to claim 2 for the preparation of salts of general formula I in which y is 1, wherein the corresponding starting compounds are substituted. 4. A process according to claim 2 for the preparation of salts of general formula I in which Z is a radical of formula II NH- ^{C 1} -alkylene, 0 II I 0 R O (B) R- 0 -CH 2 -NH-C 1-4 alkylene (and) R, 0 0 o II 11 _ IL · CH CO C £ ₉ -NH-alkyl in Ci- / ZI | «J {J R. 0 z-x -C-4-NH-C1-4 alkylene, 2 + W ¹ 4 0 (g) R, X R-G-NH-alkylene-G-64 ³ II ..... T " ^{0 and} the or (H) the alkylene group may be straight chain or branched chain and contain 1 to 3 carbon atoms; R represents a radical identical to the corresponding portion of a natural amino acid; p represents the integer 0, 1 or 2, provided that when p is 2, the alkylene groups may be the same or different and the radicals R may be the same or different O . the R representa represents a C - alquilo, alkyl group, halo-C alquilo alquilo oualkyl or aralkyl; R representa represents a C _r alquil alquil alkylene group; x represents a group of formula -GRR'R ⁿ in which R 'and R ¹ ', which may be the same or different, each represent a hydrogen atom or an alkyl group, or X represents , a group -OE = RGR ^! In which R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group, the groups containing a carbonyl radical in the formulas (a) and (c) and the substituent represented by the symbol x in the general formula ) may be attached at the 2, 3 or 4 positions of the pyridine nucleus; the groups containing a carbonyl radical in the formulas (d) and (f) and the substituent Z represented by the general formula (e) may be attached at the 2, 3 or 4 of the quinolinyl nucleus; and groups containing radicals carbonyl in the general formulas (g) è (j) and the substituent re presented by the symbol X in the general formula (h) may be attached at the 1, 3 or 4 position of the isoquinolinic nucleus, characterized in that the starting materials are substituted. 5. A process according to claim 4 for the preparation of salts of general formula I in which p is zero, characterized in that correspondingly substituted starting compounds are used. 6. A process as claimed in claim 4 for the preparation of salts of formula I in which p is 1, alkylene is methylene (-CH 2 -) and R _{2 is} - (ch ₂ ) ₂ -sch ₃ , -ch ₂ coeh ₂ or -CH-CH-CONEU, characterized in that the composition is used. is. to correspondingly substituted starting materials. 7. The process of claim 1 for the preparation of salts of general formula I in which said moiety is characterized by the absence of a hydrogen atom in an -NH- group which forms part of a functional group amide or imide or which is part of a primary or secondary amino functional group of low pXa, characterized in that the starting materials are suitably substituted. A process according to claim 7 wherein: for §. the preparation of salts of the general formula I in which y is 1, wherein starting compounds of the formula (I) are the same as those of the formula (I). 9. A process according to claim 7, for preparing 18S ration of salts of formula 1 wherein Z ^_ J QC represents a radical of general formula C- [M K ^T -alkylene-C-4 "0CH (k) RYC-FNH-alkylene-C ^ ^{1 1} yOCH0 R. (D 0 0 (m) R, C-pHH-C ~-C alquil-alkylene, R, (n) (O) - (O) - (O) 3 || ^L | ^Jp 0 B. 0 0 0 ¹¹ 1 ¹¹ COCH3-f-RH-C1-4 alkylene-OCH-, R. (P) 3 O00 $ I30 $ 00 loo L ^{ι η} '' ί ', υ IRF Thirty | I Thirty esc escuaog · j, ρ cscbOOc J 4 0 II r Cf-C alquil-C alquil-alkylene-C --OCH.. (The) r ¹¹ -τ Ε-C-F-NH-alkylene-C-3-OCH 3 || L * ι 8η I R. (r) or 0 0 0 I * Ι · Γ ¹¹ 1 COCH ₂ C-f -NH-alkylene-C-tOCH-, (s) wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R _q represents a radical identical to the corresponding portion of a natural amino acid; p represents the integer 0, 1 or 2, with the proviso that when p is 2, alkylene groups may be the same or different and E and _Q may represent the same or different radicals; Rq is alkyl-C ^ Cq, Cq-haloalkyl or aralkyl Cy -Cq ₀ C; R represents a hydrogen atom or a C1 -C6 alkyl, C1 -C6 cycloalkyl, halo-C1 -C6 alkyl, furyl, phenyl or 13Ζ phenyl having one or more halogen atoms, or lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, halo-lower alkyl, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; R3 represents a C1-4 alkylene group; X is -CONR 1 R 2, in which R 1 and R 2, which may be the same or different, each represent a hydrogen atom or a C 1 -C 4 alkyl group or X represents a â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ- the groups containing the carbonyl radicals in the general formulas (k) and (m) and the substituent represented by X in the general formula I may each be attached at the 2, 3 or 4 position of the pyridinium nucleus; the groups containing the carbonyl radicals in the general formulas (n) and (p) and the substituent represented by the symbol X in the general formula (o) may each be attached at the 2, 3 or 4-position of the quinolinic nucleus; and the groups containing the carbonyl radicals in the general formulas (q) and (s) and the substituent represented by the symbol X in the general formula (r) may each be attached at the 1, 5 or 4 position of the isoquinoline nucleus, characterized in that starting compounds are used replaced. 10. A process according to claim 9 for the preparation of salts of general formula I in which p is zero, corresponding to the starting materials of the formula (I). 11. A process according to claim 9 for the preparation of salts of the general formula I in which p is 1, alkylene is methylene (-CH ₂ -) and R _q represents a hydrogen atom or a -CH2 group, -ch (ch ₃ ) ₂ , CH-, I 3 -CH ₂ -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ , , - (CH ₂ ) ₂ -SCH ₃ -CH ₂ -CONH or -CH ~ CH ~~ _the C0NH, characterized in that use is composed correspondingly substituted starting ments. 12. A process as claimed in claim 1 for the preparation of salts of formula 1 wherein said moiety is characterized by the absence of a hydrogen atom in at least one carboxyl reactive functional group of the chelating agent, characterized in that correspondingly substituted inert compounds are used. A process according to claim 12, for the preparation of salts of general formula I, wherein y is 1, wherein the starting materials are the correspondingly substituted. 14. A process according to claim 12 for the preparation of salts of general formula I in which R ^{+ + +} representa represents a radical of general formula 0 0 ο r II 1 C1-4 alkylene-C Q-Z'-, (i) 1'9 0 0 or ^{11 11} Γ II • COCH-C-t-NH-C1-4 alkylene, (111) Raffle ιι r « ~ _Z C-12 "C-alkylene-NH QZ ^{1 1} - IL (iv) Rτ-C £-NH-alkylene-C (v) 190 1 C ₂ -C ₂ -alkyl-C ₁ -C ₂ -alkylene- R. (saw) (vii) -E-C-NH2-NH-C1-4-alkylene 0 R " (viii) or 0 0 0 II II _r H C0CH ₂ C - T "CJ-NH-alkylene - QZ '(ix) R, wherein the alkylene group may be straight chain or branched and contain 1 to 3 carbon atoms; R _Q represents a radical identical to the corresponding portion d natu ral one amino acid © · p'representa 0, 1 or 2 with the proviso that the quan p represents the number 2, the alkylene groups well be equal give or different and the radicals represented 191 3ΰφ00 30 $ ι by the symbols Κθ can be the same or different; A linear or branched C -C-C alquil alkylene group; Q represents an oxygen atom or an -NH- group; X is -CONR'R "wherein R 'and R", which may be the same or different, each represent a hydrogen atom or an alkyl group ^ Cr - C ,, or X is a group of formula -CH = ^N0R! "in which R '' represents a hydrogen atom or (I) and (iii) may each be attached at the 2, 3 or 4 position of the substituent pyridinium nucleus represented by the symbol X in the general formula (II) and the carbonyl moiety containing groups in the formulas (i) and (v) and the groups containing carbonyl radicals in general formulas (iv) and (vi) may each be attached at the 2, 3 or 4 position of the quinolinic nucleus; and the substituent represented by X in the general formula (viii) and the carbonyl radical containing groups in the general formulas (vii) and (ix) may each be attached at the 1, 3 or 4 position of the isoquinoline nucleus, characterized in that correspondingly substituted starting compounds are used. 15. A process according to claim 13 for the preparation of salts of general formula I in which J represents a radical of general formula 192 OR (x) ○ R- (I.e. II C ^-C --C --C --alkylene ιι ιι • 0 - f -NH-C1-4 alkylene - ΝΗ (Α) _η ν (χϋ) % R (xiii) (xiv) in which i _? represents a skeleton of a molecule of sugar; represents a positive integer equal to total number of hydroxy groups in the sugar molecule from which the above-mentioned skeleton is derived; represents a lower integer number by one to the total number of hydroxy groups in the mo 21 THIRTY! i TRINTA E8CUPQS *; esduoOS; the sugar molecule from which the above-mentioned skeleton is derived; each of A in each of formulas (xii), (xiii) and (xiv) may independently represent a hydroxy or 1 'group, D' being the remainder of a chelating agent containing a reactive -COH , said remainder being characterized by the absence of a hydrogen atom in said functional group -C00H in said chelating agent; and each R4 'in each of formulas (x) and (xi) may independently represent a hydroxy group or a group of formula -O-C-alkylene-NH- 0 II -W 1 0 0 Γ II " - O-C-1 to G R 1 wherein the alkylene group may be straight chain or branched chain and may contain 1 to 3 carbon atoms; R _Q represents a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, with the proviso that, when p is 0, the groups 194 ¹ 30 $ 0Q j There alkylene may be the same or different and the radicals R ₂ can be the same or different; D 'has the meaning defined with respect to the general formulas (xii), (xiii) and (xiv); R representa represents a C -C-C alquilo alkyl, halo-C -C-C alquilo alkyl or aralkyl ^and C "-C; alkyl ^; 10 'and the groups represented which contain carbonyl radicals may be attached at the 2, 3 or 4 position of the pyridine or quinolinic nucleus or at the 1, 3 or 4 position of the isoquinolinic nucleus; with the proviso that at least one of R1 and R2 in each of formulas (x) and (xi) is a group of formula 0 0 r H -1 II -O-t-C-alkylene-RH-H-C--? R -o-p-alkylene-RH TL or in which alkylene, R 1, p and R 2 and the position of the groups containing carbonyl radicals are as defined above; and with the proviso that when more than one of the radicals represents 30% to 30% r fl fl fl Id Id Id S S S S S S S S S S S S S R ^{2 '} in a given compound are the groups which contain the aforementioned carbonyl radicals, all of which groups containing carbonyl radicals in the said compound are identical, characterized in that the starting materials are the same. 16. A process according to claim 14, for the preparation of salts of general formula I, wherein p is zero, correspondingly to the starting materials. 17. A process according to claim 15, for the preparation of salts of general formula I, in which p is zero, corresponding to the starting materials of the formula (I). 18. A process according to claim 14 or 15, for the preparation of salts of formula I, wherein p is 1, alkylene is a methylene group (-CH 2 -) and R ₂ is hydrogen atom or a group -CEL, CH -CONH 2 -C 4 -alkyl, -CONH 2, -CONH 2, -CONH 2, -CONH 2, -CONH 2, 19. The process of claim 4, 5 or 6, for the preparation of salts of general formula wherein each R _c independently represents a hydrogen atom or an alkyl group C? -C? or a symbol R4 may be attached to the adjacent group of the general formula wherein the group of formula _Rr C ⁷ represents a group: O = O; each symbol R ^X R ¹ cr 6, independent entity, is a hydrogen atom or an alkyl group C - ^ - Cy or an R ^ symbol can join adjacent ^v g oup of the formula such that \ / ^R 6 the group of formula C. represents a group > C = 0: NH represents a radical of general formula or (I.e. HN NH (alk) _s -A _r rQC J where each Εγ symbol independently, represents a hydrogen atom or a C1 -C4 alkyl group; (alk) represents a straight or branched chain lower alkylene group which may additionally contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms being non-adjacent to each other. and are also non-adjacent to the atom or group represented by -A 2 -; X ~ represents the anion of a pharmaceutically acceptable organic or inorganic acid; n represents the valence of the acid anion; m 'represents a number which, when multiplied by n, is equal to 1; s is zero or 1; -A- represents an oxygen atom, a -MH- or a group of the formula -N-, in which θ represents Ro θ 4 * A C1 -C4 alkyl group; and Z is the meaning defined in claim 4, characterized in that correspondingly substituted starting compounds are used. 20. The process of claim 9 for the preparation of salts of general formula SH 5? ₅ -j HS 1 / ^r 6 ^R is i- _r -n m'X // HN NH (Ia) in which each R4 is independently a hydrogen atom or a C1 -C4 alkyl group or a symbol may be attached to the group of the formula in such a manner that the group of formula ^x r ₅ to represent : C = O; each Rg symbol, independently 19δ represents a hydrogen atom or a C1 -C4 alkyl group, or a R6 may be attached to the group of the general formula / C-Rz adjacent such that a grux JRz of formula ^S R, represents a group of formula 50 = 0: H-f _v RH. represents a radical of formula --general \ HN / NH R _f R, R, (aiq) _s -A ₂ -27qc ⁺ i HN NH or 0 = C c = o (alk) _s -A ₂ -ZQC ⁺ J + QC ⁺ J, wherein each R 4 is independently hydrogen or C 1 -C 4 alkyl; (alk) represents a straight or branched chain lower alkylene group which may additionally contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being non-adjacent to each other and also being non-adjacent in to the group represented by the symbol -A.-; represents the anion of a pharmaceutically acceptable organic or inorganic acid; n represents the valence of the acid anion; m 'represents a number which, when multiplied by n, is equal to 1; s is zero or 1; -A ₂ - represents a -CONH- group or a -CON- group in which 9 199 30 $ 00 $ 00 ¹ γ W ⁷ · » Ι ··· ~ 1 fc ', to V - * ·' ··· ¹ < Ae · - Thirty - j _EèfrUO65 1 Triitta C 1 -C 4 alkyl group; and ??? QC J is as defined in claim 9, characterized in that correspondingly substituted starting compounds are used. 21. A method according to claim 1, Claim 14 or 15, for the preparation of salts of general formula R ^SH R .-- C 5 1 R.-c B / \ 5 HN, HS p I a ^r 6? ^{R R} 6 ^R 6 is C? / Rz NH ^ ⁶ (Ia) in which each R4 is independently a hydrogen atom or a C1 -C4 alkyl group or R4 may be associated with the group of the formula - adjacent in a manner such that the group of general formula _χ / A G 'represents a group C = O; each Rz symbol, inde / ^X R ⁰ 5 and R 2 represents a hydrogen atom or a C 1 -C 4 -alkyl group or a R 4 may be attached to the group of the general formula) ## STR4 ## in such a manner that the group of formula (0) yields a group; _Z represents a radical of formula I, + or (I.e. 200 (alk) _g -A ₃ -f Q 0 ⁺ J has a straight or branched chain lower alkylene group which may additionally contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being non-adjacent to each other and also being non-adjacent to group represented by the symbol -A ^ -; X represents the anion of a pharmaceutically acceptable organic or inorganic acid; n represents the valence of the acid anion; m ¹ represents a number which, when multiplied by n, is equal to 1; s is zero or 1; "AJ represents a" group -C00-; and / ^ 7 ⁺ C-7 is as defined in claim 14 or £ 1 characterized in that the starting materials are substituted. 22. A process as claimed in claim 4, 5 or 6 for the preparation of salts of general formula > - ch ₃ s in which R ₂ and R ₂ each represent a hydrogen atom 201 or a C1-4 lower alkyl group; n 'is an integer from 0 to 3 and / or has the meaning defined in claim 4, 5 or 6, characterized in that correspondingly substituted starting compounds are used. 23. A process according to claim 4, 5 or 6, for the preparation of salts of general formula / "QC y-NH-CH ₂ CH ₂ S - C = N-NH-C-NHCH ₃ I ⁵ (lb *) c = h-kh-c-nhch ₃ I II ³ CH. s 3 where / "_ ⁺ QC / 0 is defined above in reivin claudication 4, 5 or 6, characterized in that correspondingly substituted starting compounds are used. 24.-. A process according to claim 1 for the preparation of salts of general formula cokh ₂ CH3 - (CH3) 2 - H | | d d 7ΓΤ 'VFT lithium i 1 o = c ç-o CH-CH, -, ι ί c o 1 (I.e. s W Η c. I 203 S S I I Η- H _The R ³ C0L CH? CHCONHCHOC? NH NH O Q = C 0 = 0 I I ce ₂ ch ₂ I KH NH I I o = c c = o I I ch ₂ ch ₂ 5 3β 'â †' 20 5 CH _O -CHCH _or OCH _or CH ₉ O C · id I ddd NH NH 0 = C I CH c = o I CH, έ. SH SH O 4 ^CIÍ 3 -n CH ₊ / 3 ν '<" TffíNTA - ESC UOOSή f; H 4 & _The HSCH CH NHέ. . HHCH, - CH, -SH a d. 0 -CH ₂ KEC- (or O II CH-. +/- ³ * N HSCH ₂ CNH- (Q ^ -CH ₂ 0CH ₂ CH ₂ 0õ- ⁽¹ DHCCELSH II d HCCn.ÕLH- / O \ -CH ₂ HHC- / Q + / CH-) N ^J HCCH _O SH II c ^H 3 ^C ? p _{u Z} is _NH-C-O NHCH H.C / 3 N3 , C = N , -CHH-CH-C C = H CH. r NH (CH3) _n -N 3 i CHg I d H.CV. I ³ z ^c HC ^Z | ^J SH (I.e. KH i CH ₂ υοπ ₃ I ^X CH, H.C 3 , / ΏΪ-C-NHCHSH CONH. CONHCH-CH.N Γ} '\ Br NH 1 NH 1 CO | CO | CH ₀ J 2 CH, 1 < SH 1 SH X " NH i ^H , C ^H 2 c H _q C ^z | ^J SH CH -NQ _the NHC0CH - < ^{2 2} NH i CH ₅ C < ^CH3 I CH-, SH ^J Br CONH, H-C 3 H-, C 3 AT THE / - HN I (I.e. Nik 1 or -C NH ^? 0 ¹¹ \ 0 \ _J-coni 1- 0 + 1 ^CH3 1 x ch ₃ ^ i ₂ i ₂ CH ₂ CH ₂ NHC0- (Q NH NH CH. CH Z \ N CH ₃ H _O C ^Z N / 3 3 \ H _O C 3 _{/ C} h ₃ 3 OH s vMH-C-NHCHU N-NH-C-NHCH characterized in that initial compounds are used correspondingly and in each case. 25. A process for the preparation of compounds of general formula / "DHC ⁷ II 30 $ 00] BWL 202 in which represents the remainder of a chelating agent capable of forming a complex with a metal radioisotope, said chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxy, amide and amide, said group functional group essential for the complexing properties of said chelating agent and said moiety being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups of the chelating agent; y represents the number 1 or 2; and 2 "is the reduced binoxidable form which penetrates the blood-brain barrier of the dihydropyridine redox vehicle pyridinium salt, or a pharmaceutically acceptable non-toxic salt thereof, characterized in that a salt of the general formula I prepared by the process according to claim 26. A process according to claim 25 for the preparation of compounds of general formula II, wherein said moiety is characterized by the absence of a hydrogen atom of at least one amino or hydroxy reactive functional group of the chelating agent , characterized in that correspondingly substituted starting compounds are used. 27. A process as claimed in claim 26 for the preparation of compounds of general formula II in which y is 1, wherein correspondingly substituted starting compounds are used. 28. A process according to claim 26, for the preparation of compounds of general formula II in which DHC1 represents a radical of formula 20b » , ΤΒΙΝ-ΤΛ SHIELDS J 7 NH-C1-4 alkylene, ¹ r -. ¹¹ a R _n -Ct- ₁ H-alkyl-Gi-3 | i L ι JP ⁰ (B') COCH2C-f-NH-C1-4 alkylene, R. (W ) 1-ene-C- ⁰⁰ Q II H i- 1 C-OCH₂C-J-alkylene-C j- Rf-C 1 -NH-alkylene-G -] -, 3 H ^L Q ι ^{J 0} 4 0 (and') (g ') 209 Fig. Κ _ο -0-Ρ'Ή- & 1αυί1θηο-04-, ³ ri * wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R represents a radical identical to the corresponding portion of a natural amino acid; p represents 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals R ₂ can be the same or different; the dotted line in the general formulas (a ¹ ), (b ') and (c ¹ ) indicates the presence of a double bond in the. position 4 or 5 of the dihydropyridine nucleus; the dotted line in the general formulas (d ¹ ), (e ¹ ) and (f ¹ ) indicates the presence of a du210 2 or 3 position of the dihydroquinoline nucleus; Rq re- Z represents a group of the formula -CQEE'R ", in which R 'and R", which may be the same or different, or X represents -CR = R0R "', in which R' 'represents a hydrogen atom or a C1 -C6 alkyl group, groups containing carbonyl radicals in formulas (. a ') and ⁽¹ c) and the group represented by X in formula ⁽¹ b) may, each of them being linked in position 2 or 3 _Z 4 dihidropiridínico core; the groups containing the carbonyl radicals in the general formulas (d ¹ ) and (f) and the group represented by X in the general formula (and ¹ ) may each be attached at the 2, 3 or 4 position of the dihydroquinoline nucleus; and the groups containing carbonyl radicals in the formulas (g ¹ ) θ (j ¹ ) and the group represented by the symbol X in the general formula (h ¹ ) may each be attached at the 1, 3 or 4 position of the dihydroisoquinoline nucleus, characterized in that the starting materials are substituted. 29. A process according to claim 28, for the preparation of compounds of general formula II in which p is zero, corresponding to the starting materials of the formula (I). 30. The process of claim 28 for the preparation of compounds of formula II wherein p is 1, alkylene represents methylene _(O - CH -) and R represents a hydrogen atom or d. O group -Clh, ^J CH ₀ I ³ ! -C K _{'3) k} -CH ₂ CH (CH _{3) 2,} -CH ^ Cy, -CH ₂ - •, ^ - SGEy -CH ₂ -CONH ₂ or -CH ₂ CH ₂ -CONH ₂ , characterized in that correspondingly substituted starting compounds are used. 31. A process according to claim 25 for the preparation of compounds of general formula II wherein said radical is characterized by the absence of a hydrogen atom of an -NH- group which is part of an amide or imide functional group or which forms part of a primary or secondary amino functional group of low pka, characterized in that correspondingly substituted starting compounds 32. The process of claim 31 for the preparation of compounds of general formula II in which y is number 1, characterized in that it is used with correspondingly substituted starting sites. 33. A process according to claim 31 for the preparation of compounds of general formula II in which Z is a radical of formula 0 0 H . Η C-J-1H-alkylene-C-J-r-OCHZX R. R ₀ -C p NH-C3-alkylene-H OGH3 p 1 ^L 1 ^J 0 ^h l (X ¹ ) R. d ') .14 O O II _r U C 1 -C 10 -alkylene- ⁰⁰ c C 1 -C 10 -alkylene-C 1 -C 6 -alkyl, H R _q R (I.e. r RR. R (m ¹ ) (n ¹ O ¹¹ π R-G-pKH-alkylene-C-O-OCH3 or ^L i-P i O R. (O') 0 0 o GO ΟΗρΟ - -N -NH-alkylene-C --- R. <P ') G -CH-NH-alkyl-G-J-p * -CH R, (q ') 213 (I.e. or II 1 | _Γ 0 η COCH2-NH- vM \ R. R, (s") wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R ₂ represents an identical radical and a corresponding portion of a natural amino acid; p represents 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals represented by the symbol Εθ may be the same or different; R 2 represents a hydrogen atom or a C 1 -C 4 alkyl, C 1 -C 6 cycloalkyl, halo-C 1 -C 4 alkyl, furyl, phenyl or phenyl lower alkyl, lower alkoxy, carbamoyl, alk (lower) alkylcarbonyl, lower alksnoyloxy, halo-lower alkyl, mono- (lower) alkylcarbamoyl, lower alkoxycarbonyl, di (lower alkyl) carbamoyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; the dotted line in the general formulas (k ¹ ), (1 ') and (m') indicates the presence of a double bond at the 4- or 5-position of the dihydropyridine nucleus; the dotted line in the general formulas (n '), (o ¹ ) and (p') indicates the presence of a double bond at the 2 or 3 position of the dihydroquinoline nucleus; R ^ is alkyl C₁-C₄, halo-C ^ Cr - alkyl, aralkyl or ^C 7 ^{'C10' and} 3 shows a C₁-C₄ alkylene group; X .representa a group of formula -C0KR In which R 1 and R ¹ , which may be the same or different, each represent a hydrogen atom or a C 1 -C 4 alkyl group, or X represents a group of the formula - CH ROR ^'1 in which R ^1' represents a hydrogen atom or an alkyl group C₁-L ^; groups containing carbonyl radicals in formulas ^(k1) and (m ¹⁾ and the group represented by X in formula (l ¹⁾ may each of them be attached to position 2, 3 or 4 dihidropiridínico core; groups containing carbonyl radicals in formulas (n ¹⁾ and (p *) and the group represented by the symbol X in the general formula (o ') may each be attached to the 2, 3 or 4 positions of the dihydroquinoline ring, and the groups containing carbonyl radicals in the formulas (q') and (s ¹ ) and the group represent by the symbol X in the general formula (r ¹ ) may each be attached at the 1, 3 or 4-position of the dihydroisoquinoline nucleus characterized in that the starting materials are the same. 34. A preparation according to claim 33 for the preparation of compounds of general formula II in which p is zero, wherein the starting materials are the correspondingly substituted ones. A process according to claim 33 for the preparation of compounds of formula II in which p is 1, alkylene represents a methylene group and R ₂ is hydrogen or < characterized by the use of correspondingly substituting starting compounds. replaced. 36. A process according to claim 25 for the preparation of compounds of general formula II wherein said moiety is characterized by the absence of a hydrogen atom of at least one carboxyl reactive functional group of the chelating agent, characterized in that correspondingly substituted starting compounds are used. 37. A process according to claim 36 for the preparation of compounds of general formula II in which y is 1, which is used with correspondingly substituted starting sites. 38. A process according to claim 36 for the preparation of compounds of general formula II in which zfDHG J represents a radical of general formula 216 C1-4 alkylene-C1-4 alkylene, R, (i ') CO CEL C ^ alkylene-NH --r C ¹ QZ R. (I.e. R ⁽¹ iii) 30 $ 0 to 30 $ 00 0 II FNH R-C-C-alkylene-QZ + r 3 II I ^{J Γ} Q (ii ') KH-Cf-Cj alkylene-QZ ~ ^F (iv ') 0 IL C3 -C4 -alkyl-C1-4-alkyl, (V) COCIRC-fiEH- rent no-Cj: Q-Z B, (saw') ^{C-f-KH-alkylene-C₁-1} Rf QZ (vii ¹ ) 217 "r II -1 FΓΠί -alkylene-C-C-tp 'Q' ^z ' R. 30S0Q A * ¹ ^ er & fc * - ^x *, - N "There Fig. 'Tiunta { S ji EtWtW I (vii ") ⁰⁰ B ÍIoCH.Cf -NH-alkylene-QZ CJ-- ^'R o (ix ') (ix) 213 wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R _Q is a radical identical to the corresponding portion of a natural amino acid; p represents 0, 1 or 2, with the proviso that, when p is 2, the alkylene groups may be the same or different and the radicals R 4 may be the same or different; the dotted line in formulas (i '), ⁽¹ ii) and (iii ¹⁾ indicates the presence of a double bond in position 4 or 5 of dihidropiridínico core; the dotted line in general formulas (iv '), (ν') and (vi ') indicates the presence of a double bond at the 2 or 3 position of the dihydroquinoline ring; Z 'represents a straight or branched chain alkylene group; Q represents an oxygen atom or Wherein R 'and R ", the same or different, represent, each of which is a hydrogen atom or a C1 -C4 alkyl group. and Σ represents a group of formula -CE = K0E '"in which E" ¹ represents a hydrogen atom or an alkyl group (ii ¹⁾ and the carbonyl group containing radicals in the general férmulas (i ') and (iii') can each be linked to position 2, 3 Cu 4 dihidropiridínico number; the group represented by X in formula (ν ') and the group containing carbonyl radicals in the general formulas (IV ¹⁾ and (vi') can each be linked to position 2, 3 gu 4 dihidroquinolínico core ; and the group represented skin symbol X in the general formula (VIII ¹⁾ and groups that contain 219 carbonyl radicals in the general formulas (vii ') and (ix') may each be attached to the 1, 3 or 4 position of the dihydroisoquinoline nucleus, characterized in that colorlessly substituted starting compounds are used. 39. A process according to claim 37 for the preparation of compounds of general formula XI in which DHC J represents a radical of general formula 1 5 ^(E Pn ^lv (x ') (xi ¹ ) C- [NH-alkylene-C-1: NHR. (i.e. I Rt (A) _n v MH-C1-4 alkylene-NHR. (A) _n ^v (xiii '.) 220 or NH-b L U) _n v wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R _q represents a radical identical to the corresponding portion of a natural amino acid; p represents 0, 1 or 2, with the proviso that when d p is 2, the alkylene groups may be the same or different and the radicals represented by the symbol Εθ can be the same or different; the dotted line in the general formula (xii) indicates the presence of a double bond at the 4 or 5 position of the dihydropyridine nucleus; the dotted line in the general formula (xiii ') indicates the presence of a double bond at the 2 or 3 position of the dihydroquinoline nucleus; • \ represents the skeleton of a sugar molecule; IV represents a positive integer equal to the number total of hydroxy groups in the sugar molecule from which the above-mentioned skeleton is derived; n ^v is a positive integer smaller by one than the total number of hydroxy groups in the sugar molecule from which it derives said backbone; each 221 Symbol A in each of the formulas (XII ^1), (xiii ¹⁾ '(xiv ¹⁾ and (xiv ") can independently represent a GRU well hydroxy or D', where D 'the rest of an agent chelating agent which contains a reactive functional group -COOH, said moiety being characterized by the absence of a hydrogen atom of said functional group -COOH in said chelating agent; and R ^ each symbol in each of the general formulas ⁽¹ x) and (xi ¹⁾ can independently represent a hydroxy group or a group of formula, -Q-C-alkylene-HH-C R0 0 _r II « -O-C alquil-alkylene-NH- R " or D ' 222 wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R _Q represents a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals R may be the same or different; the dotted line is defined in the same manner of the general formulas ⁽¹ xii) and (xiii ^1); D 'has the same meaning as defined for formulas garais (xii'), ⁽¹ xiii), (xiv ¹⁾ and (xiv "); Rq represents an alkyl group C₁-Cr ,, halo-Cy-alkyl or aralkyl ^and Cqo5 ^the carbonyl groups shown may be attached to the 2, 3 or 4 position of the pyridine or quinolinic nucleus or, unless otherwise specified, in the 1,3-position of the isoquinoline nucleus, provided that at least one symbol R ^ in each of formulas (x *) and (xi ¹⁾ represents a group of formula 0 0 r U -II -O-C-alkylene-NH-p-C Rn C-alkylene-NH-k-C R, in which alkylene, R 2, n, the dotted lines and the position of the groups containing carbonyl radicals are as defined above; and also with the proviso that when more than one R 2 radicals in a given compound are the aforementioned groups containing carbonyl radicals in the said compound, characterized in that correspondingly substituted starting compounds are used. 40. A method according to claim 38, for the preparation of compounds of general formula II in which p is zero, characterized in that correspondingly substituted starting compounds are used. 41. A method as claimed in claim 39; for the preparation of compounds of general formula II in which p is 0, characterized in that correspondingly substituted starting compounds are used. 42. A process according to claim 38 or 39; for the preparation of compounds of general formula II in which P is 1, alkylene represents a methylene group (-CH ₂ ") and the symbol and _Q represents a hydrogen atom or a group -CH =, ch ₃ . -CH (CH ₃ ) ₂ , -CH ₂ -CH (CH ₃ ) ₂ , -CH ₂ -CH ₂ -, - -C0'HR -CHoCHrx or -CH-CONH -, car-acterizado in that utili d 2 ^r 2 EZ - correspondingly substituted starting compounds. A process according to claim 28, 29 or 30, for the preparation of compounds of formula. general n SH Br-C ⁵ IR- ¹ p ⁵ - NH, .NH HS _R R 6 ^R _z <6 C T ^{R <r} 6 ^R6 (There is) DH in which each R4 independently is hydrogen, C1-4 alkyl or R4 may be attached to the group of formula / RJ-adjacent C such that the group of formula g £ _x ^C ? -E ^? W is a group of C = O; each R 5, independently A compound of the formula wherein R1 represents a hydrogen atom or a C1 -C4 alkyl group or a R4 may be attached to the adjacent group of the formula in such a manner that the group of the formula 0; NH. NH represents a radical of formula DH HH HH R _? R _? R _? (alk) _g -A ₁₂ -DHC 7 or (alk) -Ai-ZCHCX s wherein each R4 is independently hydrogen or C1-6 alkyl; (alk) represents a straight or branched chain lower alkylene group which may additionally contain 1, 2 or 3 oxygen atoms in the chain, these oxygen atoms being non-adjacent to each other and also being non-adjacent to the atom or a group -Af; s is zero or 1; -A- represents an oxygen atom, an -NH- group or a group of the formula -N-, in which Ro represents a C1-6 alkyl group; and DHC? ⁷ has the meaning defined in claim 28, 29 or 3θ. characterized in that correspondingly substituted starting compounds are used. 44. A method according to claim 33 wherein the step for the preparation of compounds of general formula η SH • N and HN HS p I C- ^and O c < ^b 6 .KlZ> 6 (IIa) in which each R 5 is independently a hydrogen atom or a C 1-4 alkyl group or a 5 can join the group of formula / CR - Adjacent _"r -R in such a manner that the group of formula G represents a group C = O; each R 5 independently represents a hydrogen atom or a C 1-4 alkyl group; or a symbol may be attached to the group of formula general, adjacent C-R 3 such that the group of the formula R •B, 6 represents a group = O = O; HN. DH NH represents a radical of general formula \ Hi NH _? And _? R _? (alk) _{s-A 2} OHC 7, or 0 = 0 0 = 0 ^ N ^ I (alk) _s -A ₂ - / * DHC / /"DEC./ one in each R 2, independently, represents hydrogen atom or a C 1 -C 4 alkyl group; (alk) represents a straight or branched chain lower alkylene group which may additionally contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being non-adjacent to each other and also being non-adjacent in relation to the group represented by -A ₂ -s is zero or 1; -A ₂ represents a -CONH- group or a group -CON- in which R 2 represents a C 1 -C 4 alkyl group; and / -R Hcy has the meaning defined in claim 33; characterized in that the starting materials are the same. A process according to claim 30 or 39, for the preparation of compounds of general formula SH HS ^R X lia HN NH DH 227 TRIPTY TITLE I esouoos / J | ³ gseuo & s- { wherein each R 4, independently, represents a hydrogen atom or a C1-4 alkyl group or a symbol, EP may be associated with the group of general formula / C-R adjacent in a manner such that the group of formula C, represents a group) c = 0; each F 4, independently ⁵ represents a hydrogen atom or a G1-Cr, or a R3 can be associated with the group of formula ^ ^R -NZ ctujctctíiibtí ICU niaíitíxra Quality La ± ⁰ .R, \ / ^XR wherein the group of the general formula represents a radical of general formula G4n represents a group = O = O; / ^R 6 HN DH (al <i) _s -A ~ [TWj wherein each R 2 is independently hydrogen or C 1 -C 4 alkyl; (alk) represents a straight chain or branched lower alkylene group which may additionally contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being non-adjacent to one another and being also adjacent to the group represented by -A 2 -; s is zero or 1; -A- is -COO-; and LHC7 has the meaning defined in claim 33 or 39, characterized in that starting compounds are used replaced. A method according to claim 28, 29 or 3θ, pair? the preparation of compounds of general formula / "INC, 7- _N H- _{(CH2) nI} -G = N-NH-C-NHRj C = N-1 'H-C-NHE' \ CH Ilb in which Rq and Kg each represent a hydrogen atom or a C1 -C4 alkyl group; n 'is an integer from 0 to 3 θ / DHC J ⁷ has the meaning defined in claim 28, 29 or 30, characterized in that correspondingly substituted starting compounds are used. 47. The process of claim 23, 29 or 30, for the preparation of compounds of general formula zf DHC J 7 -NH-CB ₀ CH 3. // X C = N-NH-C-HHCH-> 1-3 C = N-NH-C-F.CH, I 11 3 l o ch ₃ IId ¹ in which zfDHCJ has the meaning defined in claim 28, 29 or 3θ? characterized in that correspondingly substituted starting compounds are used. 48. A process according to claim 25, Compounds of general formula z = CFI -yHC00 ₂ (CH _{2) 2} H ? -H NH 1 o = c c = o I I CH, - CE " I am I. CONH. έ. CONH. CH, CHCH .- _The OCOCH. 4-NI 1 d. cL f " , NH NH ¹ 1 1 o = c c = o 1 1 CH, CH? 1 H s s 1 I Η H SHIELDS CC1 _O ι 3 CH, -CHCONHCHOCl] II NH NH O i l O = C 0 = O I I CH ₂ CE, II " C ¹ c kJ kJ f I Η H / ^CH 3 CH ₂ 0C- V '/ \ z CH-CH I I NH2 H I ι o = c c = o ι ι CHoCH, I Ί " ss I I II ithcch ₂ sh The \ -C00 _{(CH2) 2} -N CONH, F CH, I CH .ch ₂ nhc / ^CH 3 ^J , C ^II-Z is C l ^x w. 3 SH SH 3 CNN CH, I ^c i o = c I CH, I ^£ SH c = o I CH, I " SH CH EH i 0 = 0 OH. i SE -CHCH, OCH.CHO, I cl is. is. EH V 0 = 0 i OT-T i 2 SH ch ₂ H CH, I ^£ SH ISCH.CEH0 O> -CH.QC- NHCCH ₂ SH o ^{/ GH} 3 ¹¹ ; HSCH ₂ CNH-Z or -CH.OCH 3 MC-T? NHCCH.SH II " 0 -C1 H-CH-C CH CH 3 r-T7 C = N. NK-C-EHCH 5ϊΗ (0Η ₂ ) ₃ -ϊΗ CH. ^h 3 ^c \ I hVi SH I CH. V ^{| X} 3 SH SH I / CH3 CH. 3 CONH ,, CONICHOCHCH έ. \ (I.e. (I.e. i.e. I NH | CO co | | CH, t * CH, | ' SH SH H, C. I ^JX CH "C <' _T ch ₂ X CH, NHCOCH, -1 ' / d. d. NH I CH _P ] XCH X ^{J 1} VU SH X λ NB. c ° hh ₂ or characterized in that correspondingly substituted starting compounds are used. 49. A process for the preparation of radioactive drugs of general formula ZDHC 7 in which J represents the remainder of a chelating agent III capable of forming a complex with a radioactive metal isotope, said chelating agent having at least one reactive functional group selected from amino, carboxyl, hydroxy, amide, and imide, said functional group being not essential for the complexing properties of said chelating agent, said moiety being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups of the chelating agent; y represents the integer 1 or 2; DHC-7 represents the reduced, biooxidizable form penetrating the blood-brain barrier of the dihydropyridine-pyridinium salt redox vehicle; and M represents a radioactive metal isotope; or a pharmaceutically acceptable nontoxic salt thereof, said radioactive drug being a chelate of said radioactive metal isotope with a compound of general formula / "DHC7 _and (11) tes characterized in that a radioactive metal isotope is complexed with a compound of general formula II defined in claim 25. 50. A process for the preparation of radioactive drugs of general formula III defined in claim 49, characterized in that a radioactive drug of the general formula IV defined below is reduced in claim 69. 51. The process of claim 49 for the preparation of radioactive drugs of general formula III wherein said moiety is characterized by the absence of a hydrogen atom of at least one amino or reactive hydroxy functional group 233 of said chelating agent, characterized in that correspondingly substituted starting compounds are used. A method according to claim 51, for the preparation of radioactive drugs of general formula III in which y is 1, characterized in that correspondingly substituted starting compounds are used. 53. A method according to claim 51, For ^the preparation of radioactive drugs of general formula III in which CBHQ_7 represents a radical of general formula 0 0 Go h C-NH-alkylsulfinyl- R. '1 (? ') 'H / 0 ¹ r L ^{R-C-t-NH-alkylene-3} C-4 I ~ GO 0 r ^Ko (b ¹ ) R. R. 0 0 II _Γ l | C1-4 alkylene-C1-4 alkyl. (W) (d *) or η r II η ^R3 ~ ^^ ^{H-8lílUÍlenO} "" ^C - * o % (θ ') âit (I.e. Fig. 0 0 or II II _Γ IICQCH ₂ C - β - WH - alkyl and non - CR (I.e. (f ¹ ) ( ^hf ) R 2 is -C (O) -alkyl; 0 I u p O (H") (R) -C (O) -CH (O) 9 (j ') G-CH ₂ -alkylene-C ₁ -C ₂ -alkyl-C ₁ -C ₂ -alkylene- R, R, wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R represents a radical identical to the corresponding portion of a natural amino acid; p represents zero, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals represented by the symbol R may be the same or different; a '), (b ¹ ) and (c *) indicates the presence of a double bond at the 4- or 5-position of the dihydropyridine nucleus; the dotted line in the general formulas (d ¹ ), (e ¹ ) and (f) indicates the presence of a double bond at the 2 or 3 position of the dihydroquinoline nucleus; R3 represents a C1 -C6 alkyl group, a C1-4 alkyl group, or an aralkyl group; is an alkylene group; X represents a group of wherein R 'and R ", the same or different, each represent a hydrogen atom or a C1 -C4 alkyl group or X is -CH = (A) and (c ') and the group represented by the formula wherein R ¹ ' is hydrogen or C 1 -C 4 -alkyl, the groups containing the carboxyl radicals in the formulas by the symbol X in the general formula (b ¹ ) may each be attached at the 2, 3 or 4 positions of the dihydropyridine nucleus; the carbonyl radical containing groups in the formulas (d ¹ ) and (P) and the represented group by the symbol X in the general formula (e ') may each be attached at the 2, 3 or 4 positions of the dihydroquinoline nucleus, and the groups containing carbonyl radicals in the formulas (g ¹ ) and (j') and group represented by X in the general formula ⁽¹ h) may, each of them being attached at position 1 or 3 3rd oo 30 $ 00 4, of the dihydroisoquinolinic nucleus, L1 and L2 characterized in that the starting materials are the same. 54. A process according to claim 53, pure the preparation of radioactive drugs of general formula III in which p is zero, characterized in that correspondingly substituted starting compounds are used. Method according to claim 53 - for pre pared radioactive drugs of formula III wherein p is one, alkylene is uni methylene group (-CH? -) _q and R represents a hydrogen atom , -O correspondingly substituted starting compounds. 56. The process of claim 49 for the preparation of radioactive drugs of formula III wherein The aforementioned radical is characterized by the absence of a hydrogen atom of an -NH- group which forms part of an amide or imide functional group or which is part of a primary or secondary amino functional group of low pka, characterized in that compounds correspondingly substituted initials. 57. A process according to claim 56 for the preparation of radioactive drugs of general formula III wherein y is 1, wherein starting materials are substituted. 58. - Method according to claim 56 for the preparation of radioactive agents of formula III in which ZTrHCj ⁷ represents a radical of general formula, C4-alkyl-C4-OCH-? I P I R. I ^R i 2IZ 30 $ 00 1 ': 3' 10 (k ¹ ) ? (I.e. R-C 1 -C 4 -alkyl-NH-C d ') R, . .CO-CH-f-NH-alkyl-ene-C-4-O-CH2- R. ZsjrZ i Rn (d) (n>) U r II π C-j-NH-alkyl-C-j-r-OCH R. R (O*) R -C -Cf-NH-C-alquil alquilalkylene-CH R. CO CH _? Cf-NH-Î ± 1quot; -en-C4-T-OCHt I <JPI (I.e. yc d: , 2: 1 and (P*) ¹¹ r. Fc-C-NH-alkylene-Cl ·> CCH ^- R. (q ¹ ) (r ') 0 alkylene AND 3-CH ₂ C-O-NH-S-alkylene-O- 2N. or (s') ₂ Ç0CR C "-pNH -alkylene-C - ^ - 0CH-> (s") 1 wherein the alkylene group may be straight or branched chain and may contain 1 to 3 carbon atoms; R _q represents a radical identical to the corresponding portion of a natural amino acid; p represents 0, 1 or 2, with the proviso that when ρ is 0, the alkylene groups may be the same or different and the radicals represented by the symbol .0 R may be the same or different; R represents an or a C p-C alquilo alkyl group, a C--C ciclo cycloalkyl, a halo-C -C-C ,, alkyl, a furyl, a phenyl or a phenyl having the substituent (s); one or more halogen atoms or lower alkyl, lower alkoxy, carboxamoyloxy, lower alkoxycarbonyl, lower alkanoyloxy, halogen-lower alkyl, mono-lower alkylcarbamoyl, di (lower alkyl) carbamoyl, lower alkyl lower alkylsulfinyl or lower alkylsulfonyl, the dotted line in the general formulas (k ¹ ), (1 ') and (m ¹ ) indicates the presence of a double bond at the 4- or 5-position dihydropyridyl nucleus; the dotted line in formulas (n ') ⁽¹⁾ and (p') indicates the presence of a double bond in position 2 or 3 dihidroquinolínico core 8; R 8 represents a C 1 -C 6 alkyl group, a halogeno C 1 -C 8 alkyl _and or C 1 -C 4 aralkyl; R 2 represents a C 1 -C 4 alkylene group; X represents -CONB R ', in which R' and R ", the same or different, each represent a hydrogen atom or a C -C-C alquilo alkyl group, or X represents a group of formula general -CH-NOR ^'1' in which R '' represents a hydrogen atom or an alkyl group C₁-C₄; groups containing carbonyl radicals in formulas (k ') and (m ¹⁾ and the group represented by the symbol X in the general formula (1 ^r ) can each, nico; the groups containing the carbonyl radicals in the general formulas (n ¹ ) and (p ') and the group represented by the symbol X in the general formula ( ¹ ) may each be attached at the 2, 3 or 4-position of the dihydroquinoline nucleus ; and the groups containing carbonyl radicals in the general formulas (q *) and (s ¹ ) and the group represented by X in the general formula (r ¹ ) may each be attached at the 1, 3 or 4 position of the nucleus dihydroquinoline, characterized in that correspondingly substituted starting compounds are used. 5. A process according to claim 5, for the preparation of radioactive drugs of general formula III in which p is zero, characterized in that correspondingly substituted starting compounds are used. The process according to claim 58 for the preparation of radioactive drugs of formula III in which p is 1, alkylene represents a methylene group (-CEL-) and R ₂ is of hydroge- characterized in that correspondingly substituted starting compounds are used. 61. A method as claimed in claim 49, for the preparation of radioactive drugs of general formula III wherein said radical is characterized by the absence of a hydrogen atom of at least one functional carboxyl group reacted with said chelating agent, correspondingly substituted starting compounds. 62. A process according to claim 61 for the preparation of radioactive drugs of formula III in which y is 1, wherein starting materials are substituted. 63. A process according to claim 61, for the preparation of radioactive drugs of general formula III in which R 2 represents a radical of formula C-4-Q-Z '-, 1 R. X (i ') ^M R ^ -C-alkylene-HNP-Cf - ¹ QZ JL j | jp 0 R (i *) C 1 -C 10 -alkylene-C 1 -C 10 -alkyl. Il 1 E (iii ') U || C 1 -alkyl and -N-C 1 -Z ¹ R ¹ 1 (iv ') R ¹ -C ² -alkylene- 0 0 G-OCH₂CH₂C al-Alkylene- R 0. And _ft (ν ') ⁰ (saw") ⁰ ί! η r II η C-pNH-alkylene-C1-4-alkyl (vii ¹ ) ⁰ Ç - £ NH ^- c? Q-Z ¹ R_ ,. _Ί 2Ν. (vii ^t! ) (ix ") wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; Εθ represents a radical identical to the corresponding portion of a natural amino acid; p is 1, 1 or 2, with the proviso that when p represents the number 2, the alkylene groups may be the same or different and the radicals represented by the symbol R 2 may be the same or different; the dotted line in formulas (i '), ⁽¹ li) and (iii') indicates the presence of a double bond in position 4 or 5 of dihidropirridínico core; the dotted line in general formulas (iv '), (ν') and (vi ¹ ) indicates the presence of a double bond at the 2 or 3 position of the dihydroquinoline nucleus; Z ¹ represents a straight or branched chain alkylene group wherein R 4 represents an oxygen atom or an -NH- group; R ^ is an alkyl group _C₁-Y, halogen-alkyl - ^ - Cr, aralkyl or C ^ -C ^ g ^ R represents an alkylene group C₁-C₄; X represents a group of the formula -CONO wherein R 'and R', which may be the same or different, each represent a hydrogen atom or a C1 -C4 alkyl group or X represents a group of -CH = N0R '"whereinR'" represents a hydrogen atom or an alkyl group C _y -C _y; the group represented by X in formula (II - ¹⁾ and the group containing carbohydrate radical ⁿ Nile in formulas ⁽ⁱ¹⁾ and (iii ') can each of them being bonded at position 2, 3 or 4 dihydropyridine nucleus; the group represented by X in formula (ν ') and the group containing carbonyl radicals in the general formulas (IV ¹⁾ and (vi ¹⁾ may each of them be attached at the 2, 3 or 4 dihidroquinolínico core ; and the group represented by X in the general formula (VIII ¹⁾ and the groups W 2.44 ^J - - -lirt Thirty- ^fifth _. ! SHIELDS- I which contain carbonyl radicals in general formulas (v ¹ ) and (ix ¹ ') may each be attached at the 1, 3 or 4 position of the dihydroisoquinoline nucleus, characterized in that correspondingly substituted starting compounds are used. 64. The process of claim 62, for the preparation of radioactive drugs of the general formula IIP in which Z'HCl represents a radical of general formula (I.e. R ⁽¹ xii) (xi *) (A) _n v . 4 ^ ¹¹ r ¹¹ π '\ - C-trNR-C1-4 alkylene-NH- _f -4 R, (A) _n v (xiii) 0 0 C-f-KH-alkylene-C-J-NHE. (A) v OR (xiv ¹ ) 24 -CH 2 -HH-al U) _H v (xiv '5 wherein the alkylene backbone may be straight-chain or branched and contain; carbon atoms; R _Q represents a radical identical to the corresponding portion of a natural amino acid; p represents 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals R may be the same or different; the dotted line in the general formula (xii ') indicates the presence, of a double bond, at the 4 or 5 position of the dihydropyridine nucleus; the dotted line in the general formula (xiii *) indicates the presence of a double bond 5 or in position 2 of the nucleus dihidroquinolínico [j repre \ / _and * ' sits the skeleton of a sugar molecule; ^lv n represents a positive integer equal to the total number of hydroxy groups in the sugar molecule from which said skeleton derives; n ⁷ represents a lower positive integer in a total number of hydroxy groups in the sugar molecule from which the above-mentioned skeleton is derived; each of A in each of formulas (xii '), (xiii), (xiv *) and (xiv ") may independently represent a hydroxy or S' group, with L 'being the remainder of a chelating agent which contains a reactive carboxyl functional group -COOH, said moiety being characterized by the absence of a hydrogen atom from the above- of the functional group -C00H in the cited chelating agent; and each R4 in each of the general formulas (x ^f ) and (xi '), may independently represent a hydroxy group, a group of formula, 0 0 , _R1 , I -O-C alquil-C alquil-C alquil-alkylene R0 0 Γ 1 'Ί O-t-C-alkylene-RH-p-p- R II XYY alkylene-NE | -l · -c4p ^w 1 or D ¹ wherein the alkylene group may be straight or branched chain and may contain 1 to 3 carbon atoms; R _q represents a radical identical to the corresponding portion of a natural amino acid; p represents 0, 1 or 2, with the proviso that when p is 2, alkylene groups may be equal or different and the radicals represented by the symbol can be the same or different; the dotted line is the 2.4.Ζ as defined for the general formulas (xii ') and * (xiii'); D 'is as defined for the general formulas (xii'), (xiv ') and (xiv') ^, Pp represents a C1-6 alkyl, halo- Or aralkyl; and the carbonyl groups shown may be attached at the 2, 3 or 4 position of the pyridine or quinolinic nucleus or, unless otherwise specified, at the 1, 3 or 4 position of the isoquinoline nucleus; with the proviso that at least one of R1 'in each of the formulas (x') and (xi ') represents a group of formula -O-O-alkylene-M R-, -O-alkylene-HH or 0 (I.e. 248 -Ο-p · C-alkylene-PH j - ¹ C P 3θ οα 30S0Q wherein alkylene, R _q , p, R p the dotted lines and the position of the groups containing carbonyl radicals are as previously defined; and with the proviso that when more than one of the radicals represented by the symbol on a given compound are the above-mentioned groups which contain carbonyl radicals, all such groups containing carbonyl radicals in the said compound are the same, characterized in that correspondingly substituted starting compounds are used. 65. A process according to claim 63 for the preparation of radioactive drugs of general formula III in which p is zero, corresponding to the starting materials of the formula (I). A process according to claim 64 for the preparation of radioactive drugs of formula III in which p is zero, corresponding to the initiation of correspondingly substituted starting compounds. 67. - Method according to claim 63 or 64 · for the preparation of radioactive agents of formula III wherein p is one, alkylene is a methylene group (-CEb, -) and R _q represents a hydrogen atom; T-JtftfTA ESOUDOS 2ki characterized in that the starting compounds are optionally substituted coffers. A process according to claim 49 for the preparation of radioactive drugs of formula III in which M is technetium-99nium, characterized in that correspondingly substituted starting compounds are used. 69. A process for the preparation of radioactive medicaments of general formula - ~ / \ C ⁺ 7 ^{ι4Γ η} IV V in which the remainder of a chelating agent is capable of forming a complex with a radioactive metal isotope, said chelating agent having at least one reactive functional group selected from amino, carboxy, hydroxy, amide and imide, said functional group being not essential for the complexing properties of said chelating agent, said moiety being characterized by the absence of a hydrogen atom of at least one of said chelating agent reactive functional groups; represents the number 1 or 2. Z 2 represents the ionic and hydrophilic form of the pyridinium salt of a redox vehicle dihydropyridine pyridinium salt; forming a pharmaceutically acceptable organic or inorganic acid; n represents the valence of the acid anion; m represents a number which, when multiplied by n, is equal to y; and M represents a radioactive metal isotope; said radioactive material of formula IV being a quot; quot; of said radioactive isotope metal with a salt of formula general I in which -n Ψ - , and? Z ", QC, X, n and m have the meaning defined above, characterized in that (a) a radioactive metal isotope having a salt of general formula I defined in claim 1; or (fc) of oxidizing a radioactive drug of general formula III defined in claim 49. 70. A process according to claim 69, for the preparation of radioactive drugs of general formula IV, wherein said moiety is characterized by the absence of a hydrogen atom of at least one amino or hydroxy reactive functional group of the chelating agent, characterized in that corresponding starting compounds substituted. A method according to claim 70, for the preparation of radioactive drugs of the general formula IV in which y is number 1, characterized in that correspondingly substituted starting compounds are used. 72. A process according to claim 70, for the preparation of radioactive drugs of the general formula IV in which Q ⁺ represents a radical of general formula II II THE (3) (B) 251 o ιι ιι Ο Ο CH 2 C H-alkylene Βίο) (I.e. (g) O ¹¹ τ C1-4 -alkyl I ^{p Ko} 30ϋΰϋΰ C-pHH-alkylene-Î']] - (d) Fc (f) (H) ~ ⁰ 1 ² Z '\ r ¹¹ 1 R 2 is selected from the group consisting of: OR wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R _q represents a radical identical to the corresponding portion of an amino acid 252 Natural; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals represented by the symbol θ may be the same or different; R1 represents R e and R,, which may be the same or different, each represents a carbonyl radicals of general formulas (a) and (c) and the group represented by X in the general formula (b) may each be attached at the 2, 3 or 4 position of the pyridinium nucleus; the groups containing the carbonyl radicals in the formulas (d) and (f) and the group represented by the symbol X in the general formula (e) may each be bonded at the 2, 3 ^or 4 positions of the quinolinic nucleus and the groups (g) and (j) and the group represented by the symbol X in the general formula (h) may each be attached at the 1, 3 or 4-position of the isoquinoline nucleus, characterized in that the starting compounds are optionally substituted. The process of claim 72j for the preparation of radioactive drugs of the general formula IV wherein p is zero, corresponding to the starting materials of the present invention. 74. A process according to claim 72 for the preparation of for the preparation of radioactive drugs of the general formula IV in which p is 1, alkylene is a methylene group (-CY-) and E 'is a hydrogen atom, by the use of correspondingly substituted starting compounds. A process according to claim 69, for the preparation of radioactive drugs of general formula IV wherein said moiety is characterized by the absence of a hydrogen atom of an -NH- group which forms part of an amide or imide functional group or which forms part of an amino functional group , primary or secondary, of low pka, characterized in that it uses correspondingly substituted starting compounds. 76. A process according to claim 75, for the preparation of radioactive drugs of the general formula IV in which y is 1, characterized in that correspondingly substituted starting compounds are used, 77. A process according to claim 75, for the preparation of radioactive drugs of general formula IV in which R7 represents a radical of general formula 0 O (k) (D (q) 4-c NH-alkylene-C-J-OCHR, O -Alkyl-C 1 -OCH 2 u R fc (r) ⁰ wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; Εθ represents a radical identical to the corresponding portion of a natural amino acid; p represents 0, 1 or 2, with the proviso that, when p is 0, the alkylene groups may be the same or different and the radicals R ₂ can be the same or different; R ^ repre sits alkyl C ₁ -C _y alkyl or halo- C ^ aralkyl -CjqJ R represents a hydrogen atom or an alkyl C? -C ?, C₁ to C₆ cycloalkyl, halo-alkyl it _C₁-y, furyl, phenyl or phenyl having as a substituent te (s) lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, halogen-lower alkyl, mono-lower alkylcarbamoyl, di (lower alkyl) carbamoyl. (lower) alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; Represents R ^ _O ^ roup slquileno CJC; X represents a group of formula -COhF'R "wherein R 'and ^{R! L,} which may be identical or different, represent each a hydrogen atom or an alkyl GRU well -C ,, or X is Cr a group of formula -CH NQR ^{1 '1'} in which R '"represents a hydrogen atom or an alkyl C? -C ?; groups containing carbonyl radicals in the general formulas (K) and (m) and the group represents - by the symbol X in the general formula (1) may each be attached at the 2, 3 or 4 position of the pyridine nucleus; the groups containing the carbonyl radicals in the general formulas (n) and (p) and the group represented by the symbol X in the general formula (o) may each be attached at the 2, 3 ^or the quinolinyl nucleus; and the groups containing the carbonyl radicals of the general formulas (q) and (s) and the group represented by X in the general formula (r) may each be attached at the 1-position, 3 or 4 of the isoquinolinic nucleus, characterized in that correspondingly substituted starting compounds are used. 73. The method of claim 77, for the preparation of radioactive drugs of general formula IV in which p is zero, characterized in that correspondingly substituted starting compounds are used. 79. A process according to claim 77, for the preparation of radioactive agents of formula IV in which p is 0 Number 1, alkylene is a methylene group (-CB -) _n and R represents a hydrocarbon atom QV £ by the use of correspondingly substituted starting compounds. 30. The process of claim 69 for the preparation of radioactive drugs of general formula IV wherein said moiety is characterized by the absence of an atom of hydrogen of at least one carboxyl reactive functional group 2Z of the chelating agent, characterized in that correspondingly substituted starting compounds are used. 81. The process of claim 80 for the preparation of radioactive drugs of the general formula IV wherein y is 1, wherein starting materials are suitably substituted. A process according to claim 80 for the preparation of radioactive drugs of the general formula IV in which Z 1 ⁺ 7 represents a radical of general formula IJH-C1-4 alkylene-Q-2 'N R ~ ⁰ O (ii) 0 0 0 (iii) 0 (iv) THE. Γ 1 '1 -NH-alkyl-C 1-4 alkyl-R ¹ , (vii) + N-R-C-f-NH-alkylene-G ³ ~ ll I 0 R (viii) is -CH2 -NH-alkylene-C1 -C4 -alkyl; R, 1 (ix) wherein the alkylene group may be straight chain or branched and contains 1 to 3 carbon atoms; R _q represents a identical to the corresponding portion of a natural amino acid; p represents. 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals R may be the same or different; Z ¹ represents a straight chain or straight chain alkylene group; q represents an oxygen atom or an -NH- group; R 2 represents a halogen-C 1 -C 4 alkyl group; or aralkyl Eg _re p _rese nta an alkylene group C ^ alkyl; X represents a group of the formula -CONR 'R''in which R' and R ', which may be the same or different, each represent a hydrogen atom or a C1 -C4 alkyl group, or X has a group of formula -CH = N0R ^'n wherein R''represents. a hydrogen atom or a C1 -C6 alkyl group, represented by X in the general formula (ii), and the carbonyl radical containing groups in the general formulas (i) and (iii) may each be attached in the 2,3 or 4 position of the pyridine nucleus; the group represented by the symbol X in the general formula (v) and the carboxyl radical-containing groups in the general formulas (iv) and (vi) may each be attached at the 2, 3 or 4 position of the quinolinic nucleus; and the group represented by X in the general formula (VIII) and those groups ^- containing carbonyl radicals in formulas (vii) and (ix) can each of them being attached at position 1, 3 or 4 of the isoquinoline nucleus, characterized in that the starting materials are substituted. 83. The process of claim 81 for the preparation of radioactive drugs of formula IV in which  € ƒâ € ƒâ € ƒQ2 is a radical of general formula : 6θ ΚΓ, ρ __ i si KI eVoVdCí (B \) ₅ (x) ( _E , + (You) oF _t , z i R ^b l (C 1 -C 4) alkylene-C 1 -C 4 -alkylene- OR And 0 II (I.e. (A) v 'n Ϊ. θ-c-pNH-alkylene-Cpp-NH-h i R. (A) _n v (A) v n / 'saw wherein J represents the skeleton of a sugar molecule; . n ^lv represents a positive integer equal to to the total number of hydroxy groups in the sugar molecule from which the backbone is derived; n ^v is a positive integer less than 1 in the total number of hydroxy groups in the sugar molecule that this skeleton is derived; each A symbol on each. of the general formulas (xii), (xiii) and (xiv) may independently represent a hydroxy or Τ 'group, 261 the remainder being a chelating agent containing a reactive -COOH functional group, the remainder being characterized by the absence of a hydrogen atom of said functional group -COOH in said chelating agent; and each R1 'in each of formulas (x) and (xi) may independently represent a hydroxy group or a group of formula wherein the alkylene group may be straight or branched chain and contain 1 to 3 carbon atoms; R represents a radical. identical to. corresponding portion of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the radicals represented by R may be the same or different; D ¹ has the meaning given in relation to the general formulas (xii), (xiii) and (xiv); R 8 represents a C 1 -C 8 alkyl, hyslogene-alkyl C? -C? or (C -C-C ar) aralkyl which contain carbonyl radicals may be attached at the 2, 3 or 4 position of the pyridine or quinolinic nucleus, or at the 1, 3 or 4 position of the isoquinolinic nucleus; with the proviso that at least one of R1 and R2 in each of formulas (x) and (xi) is a group of general formula 0 II  O-α-b-alkylene-lH ^B OV I R-, 0 II -cfc- elquileno-I ^T H - ^ - CR_ or THE. I B 1 wherein alkylene, Βθ, p and R e and the position of the groups having carbonyl radicals have the meanings defined above; and with the proviso that when any of R 1 'in a given compound represents the aforementioned groups containing carbonyl radicals, all such groups containing carbonyl radicals in the said compound are identical, characterized in that the starting compounds are initially used as starting materials. 84.- Process according to the. claim 82, for the preparation of radioactive drugs of general formula IV in which the p represents zero, characterized in that it is used. correspondingly substituted starting compounds. 6. A process according to claim 83 for the preparation of radioactive drugs of formula IV wherein p is zero, wherein the corresponding starting compounds are substituted. A process according to claim 32 or 835 for the preparation of radioactive drugs of formula IV in which p is 0, alkylene is a methylene group (-CH ₃ -) and the symbol represents a hi < Accordingly, the starting compounds are preferably substituted. 87. A process according to claim 69 for the preparation of radioactive drugs of formula IV in which the symbol is technetium-99m, characterized in that correspondingly substituted starting compounds are used. 88. A method as claimed in claim 53, 54 55? for the preparation of a radioactive drug which is a chelate of a radioactive metal isotope with a compound of general formula DH lia in which each E _r , independently, represents a hydrogen atom or a C1 -C6 alkyl group, _y or B- may be associated with the group of formula J / C-PL · 264 R _c in such a manner that the group of formula • R _c represents a group C = O; each Rg, independentemen te represents a hydrogen atom or an alkyl group θ1 "θ7 ^{or 11151 s} i ^M fr L ° may be associated with the FoR general formula group / C-Rg adjacent in such a way that _O roup of general formula b represents a group c = 0; HH. . JH ^R6 represents a radical of general formula (I.e. HH HH λ-A R? R? R? (alk-A-H-DHC-7 or (alk) _s -A ₁ - / ÊiHCy wherein each R3 is independently a hydrogen atom or a C1 -C6 alkyl group; (alk) represents a straight or branched chain lower alkylene group which may optionally contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being non-adjacent to one another and also being non-adjacent with respect to the atom or group represented by the symbol -A ·, -; s is zero or 1; -A- represents an oxygen atom, a -HH- or a group -H- in which Rg represents Ro a C1 -C4 alkyl group; and Z "DHC7 has the meaning defined in claim 53; 54 or 55? characterized in that correspondingly substituted starting compounds are used. 39. A process according to claim 8 for the preparation of a radioactive drug which is a chelate of a radioactive metal isotope with a compound of general formula SH 26 ^ one wherein R ^ cacla símbnlo independently representí átomr 'hydrogen or an alkyl group C ^ -G ^, R or _R can be associated with the group of formula / b-rpg adjacent such that the group Gee formula _R ς \ V v v / 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- W or a R 4 group may be associated with the adjacent group of the general formula wherein R 3 and R 4 are independently selected from the group consisting of hydrogen, po of formula C represents a C-O group; ^And is NH represents a radical of formula DH represents a group C = O; each R 4, independently RH \ ln n iii; 0 = 0 I R _? R _? (alk) _g -A ₂ - / "DHC 7 _} or / w c = o (alk) _s -A ₂ -Z ₁ K C .N ZDHcy wherein each R 4, independently, represents a hydrogen atom or a C1-4 alkyl group, (alk) represents a straight chain or branched lower alkylene group r30 which may additionally contain 1 or 3 oxygen atoms in the chain, said oxygen atoms being non-adjacent to one another and also non-adjacent to the group represented by the symbol -A. s is zero or 1; ^ -A ^- is -CONH- or a group of formula -CO-T-, in which Eq represents, a Rr C -C-C alquilo alkyl; and DHG7 has the defined meaning in claim 5θ ' characterized in that starting compounds are optionally substituted. A method according to claim 63 or 64, for. s preparation of a radioactive drug which is a chelate of a radioactive metal isotope with a compound of general formula in which each R4 is independently a hydrogen atom or a C1 -C4 -alkyl group or a R4 -alkyl group may be associated with the group of the formula / CR2, adjacent in a manner such that the group of formula \ d. â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒOR 'represents a group = O = each R 4, in dependently represents a hydrogen atom or a C1 -C4 alkyl group; or R4 may be associated with the group of formula adjacent in a manner such that the group of general formula diester of general formula / NH And _? R _? (alk) _g -A - / - DHC 7 OR (alk) J ·> a straight or branched chain lower alkylene group which, in addition, may contain 1, 2 or 3 oxygen atoms. chain, said oxygen atoms being non-adjacent to each other and also non-adjacent in as defined in claim 63 or 64, characterized in that correspondingly substituted starting compounds are used. 91. A process for the repair of radioactive drugs according to claim 88, characterized in that the radioactive metal isotope is the oxotecnate-99m 92 ion. 10. A process for the preparation of radioactive drugs according to claim 89, characterized in that the radioactive metal isotope is used, the oxotecnate-99m ion. 5. A process for the preparation of radioactive drugs according to claim 90, characterized in that the radioactive metal isotope is used as the oxotecnate-99m ion 94. A process as claimed in claim 53, 54 or 55; for the preparation of a radioactive drug which is a chelate of a radioactive metal isotope with a compound of general formula KH-7 (CH _{2) n,} \ Il X-C = N-NH-C-NHR C = N-RH-C-UHR, iib CH 2 wherein R 2 and R 3 each represent a And n is an integer from 0 to 3 and Z is as defined in claim 53, 5 * + or 5, characterized in that the starting materials are the same. Process for the preparation of radioactive drugs according to claim 94, characterized in that radioactive metal isotope is used as the oxotecnate-99s ion 96. A process as claimed in claim 53, 54 or 55 for the preparation of a radioactive drug which is a chelate of a radioactive metal isotope as a compound of general formula ?  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ -NH-C-NHâ, ^... where / "DIICJ ⁷ is as defined in claim 53, 54 or 55, characterized in that correspondingly substituted compounds are used. 97. A process for the preparation of radioactive drugs according to claim 96, characterized in that the radioactive metal isotope is the oxotecnate 99-ion. 98. A method as claimed in claim 72 wherein: 73 or 74 / psr the preparation of a radioactive drug which is a chelate of a radioactive metal isotope with a salt of general formula SH HS X, KA and R Rz / ^{6 x} Rz ia , ( ^R 6) HM NH A A in which each R 2, independently, represents a hydrogen atom or an alkyl group or a symbol Râ,, may be associated with the group of formula adjacent in a manner such that the group ^X ' 5 represents a group C = O; each R ^ symbol ^J independently mind, represents a hydrogen atom or an alkyl group it or symbol R ^ can be associated with the group of general formula (O) -R6 in such a way that the G6 represents a group / G = O; HN, HH R, represents a radical of general formula HN NH R "R" R 2 (alk) _s -A ₁ - / QC QC or (alk) _s -A ₁ - / ^"+ 6C 7 wherein each R 'is independently a hydrogen atom or an alkyl (alk) group represents a straight or branched chain lower alkylene group which may additionally contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms mentioned are not general which are relative to each other and are also non-adjacent to the atom or group represented by the symbol -q-; X "represents the anion of an acceptable organic or inorganic acid in pharmacy; n represents the valence of the acid anion; m 'represents a number which, when multiplied by n, is equal to 1; s is zero or 1; represents an oxygen atom, a -HH- group or a halide group H- in which θ represents a C1-6 alkyl group; Hp O and [QCP] J is as defined in claim 72, 73 or 74, characterized in that correspondingly substituted starting compounds are used. 99. The process of claim 77 for the preparation of a radioactive drug which is a chelate of a radioactive metal isotope with a salt of general formula SH R, L HS _n IZ ^XL 6 \ R, -7) Ia Q ' .HH " ^L 6 Sr one wherein each R ^ independently, represents hydrogen or an alkyl group Cq-Ογ, or an R _r may be associated with the group of the formula, groups R ^ 0- adjacent group such that the group of formula Râ _,, independently represents a hydrogen atom or a Câ, â, <â, † alkyl group or a Râ,, may be associated with the group of formula: rt Sn ZÍ Rz adjacent in a manner such that the group of formula represents a) = O; > represents a radical of general formula HH BH Ç PC (alk) _g To ₂ - [Q0 ⁺ J OR (alk) -1 ₉ -Z "QG ^v ] 271 (I.e. HN NH o = c c = o f + c ⁺ 7 _y wherein R independently represents a hydrogen or an alkyl group a'tomo Cq-C _y; (alk) represents a straight or branched chain lower alkylene group which may additionally contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being non-adjacent to one another and being also not adjacent in to the group represented by the symbol -A ₂ ";X" represents the inorganic anionic organic acid in pharmacy; n represents the valence of the acid anion; m 'represents a number which, when multiplied. by n, is equal to 1; s is zero or 1; -A ₂ represents a -CONH- group or a group of the general formula -COHR 9 ₊ 9 wherein R ^ is alkyl C? -C · _y; and ZQC ' ⁷ has the meaning defined in claim 77; characterized in that correspondingly substituted starting compounds are used. 100. The process of claim 82 or 83 for the preparation of a radioactive drug which is a chelate of a radioactive metal isotope with a salt of general formula SH HS Ia 2? 2 SCREWS _, SHIELDS wherein each R _c independently represents a hydrogen atom or an alkyl group pG-B ?, or a symbol, _ 0 may be associated with the group of formula / ^ CR \ BB adjacent groups such that the group of formula ^R 5 represents a group C = O; each R3 independently is hydrogen, C1-4 alkyl or R4 may be associated with the adjacent group of the formula wherein the general formula C , / ^B 6 AND, represents a group / G = O; H z p, 7W represents a radical of general formula \ HN NH xir, R7 R4 (alk) QG J or (alk) _g -Ay / ^- ^ C ⁺ J in which each R4 is independently a hydrogen atom or a C1 -C4 alkyl group (alk) represents a straight or branched chain lower alkylene group which may additionally contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being non-adjacent to each other and also being non-adjacent to the group represented by -Ay; λ "represents the anion of an acceptable organic or inorganic acid in pharmacy; it does not represent the valence of the acid anion; m 'represents a number which, when multiplied by n, is equal to 1; s is zero or 1; -A- is -COO-, and 4 " / J ~ ⁷ has 0 qG defined in claim 32 or 83, 30500: f30500 ESÇUO & S 2za for the preparation of a radioactive drug which is a radioactive metal isotope with a salt of formula characterized in that the starting materials are the same. A process for the preparation of radioactive drugs according to claim 98, characterized in that the radioactive metal isotope is used as the oxotheca-99m ion. 102. A process for the preparation of radioactive drugs according to claim 99, characterized in that the radioactive metal isotope is the oxotecnate-99m ion. - A process for the preparation of radioactive drugs according to claim 100, characterized in that the radioactive metal isotope is the oxotecnate-99m ion. 104. A process according to claim 72, 73 or 7¼ chelate of general Ph II c = n-nh-c-phr ₃ 1 1 C = K-NH-C-NHR _O 1 II P Ib cm in which 8 R1 and R2 each represent a hydrogen atom or a C1 -C4 alkyl group; n 'is an integer of 4 to 4; ro from 0 to 3 θ Z QC J has the meaning defined in claim 72, 73 or 74, characterized in that the starting compounds are substituted by the same. A process for the preparation of radioactive drugs according to claim 104, characterized in that 274 1 " radioactive metal isotope, or 99m-oxotecnate ion. 106. The process of claim 72, 73 or 74 for the preparation of a radioactive drug which is a chelate of a radioactive metal isotope with a salt of general formula Z-QC-7-NH-CH ₂ CH ₂ s N-NH-C-NHCH. Ib ¹ , + C-NH-NH-C-NHCH-. I ll 3 | g ch ₃ in which 20 has the meaning defined in claim 72, 73 or 74, characterized in that correspondingly substituted starting compounds are used. 107. A process for the preparation of radioactive drugs according to claim 106, characterized in that radioactive metal isotope, or 99m-oxotecnate ion. 108. A process according to claim 49 for the preparation of a radioactive drug which is a complex (chelate) of the oxoteenate-99m ion with a compound of formula CONEL , NHC0, -CHC00 CH (CH) .- /? 1 2 1 2 ^ _ NH CH -CHCH _the 0C0CH _the Ni 2 1 2 2 NH NH o = c / = Uíx * L · I " c = o I 1 CH, CH " I I ss CC1 / ^CH3 3050Q ¹ 30S00 J fr ^L π ···. J 'M' L. Cirnas j 0 ³ CH ^2; H -CHCONHCHOC-- ZI NH NH 0 I I 0 = 0 0 = 0 -and ch ₂ oc-Z / ^IIC 3 EC, \ z \ z (I.e. CH CH i f 0 = C C = 0 CH CH I ² I "ssf 1 Η H • COO (CIA) CONE, 2'2 _{z CH3} r NH 1 CH. ¹¹ // gh ₂ nhc-Z Ί1 K3C, h, <X | ⁱ SH NV (I.e. CH, , CHP SH CHΓ Γ " CH, H ^r I ^£ 3 ^v V H ( ^{Z 1)} 3 ^v s ⁿ H _{2 0} C NH 1" CH _p I> 3 Xh SH ^u 3 CH, ^H 3 ^and x 1, II F A SH X • · *. 276 ι CHI NH C = 0 ι CNd CH j d GÍL · SH SH I ' ^£ CHI CRN I ^d SH CH, - 1 1 ^is -CHCHqOCH I NH 1 N ^; W L = O I EC Hi 1 I ^d SH SH d d -CH ₂ 0G-, NHCCH.SH 11 / ^CH 3 HSCH ₂ CNH- HHCCH3 SH II HCCh-SH II 0 ce cnh- ₂ / Q \ -l IIK ₂ H _n G. CH 0 .G = N 11 / , -CH2 -H NH-C-NHCEL / 11 3 W; / ^{c =} 3 11 co CO i CH, I ' SH CH ,. I * SH / " NH I CH, ^H 3. ' □ _c ^K 3 ^C SH (I.e. ch ₃ CH, NHCOCH ₉ -H £ d NH CH, W. ^{J 1} SH 3 (I.e. -C W (I.e. ΝΗκ Níi CONH, or ^H 3 ^C \. \ -Conh-ch ₂ ch ₂ characterized in that correspondingly substituted starting compounds are used. 109. Process according to the. claim 69, for the preparation of a radioactive drug, which is a complex (chelate) of the 99m-oxotecnate ion with a salt of formula CONH, CH, -CHCOO (CH3), -N + * Q J eX j Z 6 \ - / KH I 0 = C You F C = G 1 I CH, CH. j | έ. CONH n I N0 II • e0 H 0 l / xjl T.t S fi . C -CE. SH CH _n -CHCH, -> OCOCCE, -N 1 NH 0 = C 1 CH ₀ 1 d s I H I NH I c = o I CH ,. 1 £ s 1 H Br ^s · · « I CH, 0 li KSCH ₂ uNH CH. hi HH C = Q I CH, CH ₂ 0C \ CH- 1 NH / CH 1 HH 1 0 = C 1 C = Q ι | GH. CH. | | s I s I 1 H 1 H C00 _{(CH2) 2} _ _n <^ hhcch, -sh II 0 conh ₂ CH. 3 HH ι CH, ^H 3 ^C \ I ' I 3 H .'II l Cl IR. IR. SH 3 • · · 280 CH 2 - I έ. (I.e. -CHC 1 HH CH ,. ι £ - CH _O CKp CH3 1 1 ^d SH SH 30 $ 00 Ί30S00 bwwt | Γρ Ι * - * Γ ^κ V 'i Eur-lex.europa.eu eur-lex.europa.eu t pFL Thirty · [.Trinta ¹ ESCUDOS j- j_ESCUDOS 0 -CNE-GH = Cs Ρ. ^H 3 ^C NH-CH-NHCH. h ₃ c C = I1 NH-C-NHCH. II 3 CH 3 CH- nr Ocelot-cilZ O via Oi. / 2 CGNH _{2 z} gh, .nhcoch ~ -nq r NH r GH. HZ , /, NH CH, I ZhZ I \ JL SH 3 H ₂ N NH · 0 I CH -C NH or NH NH | | GO co | GH ,, | CH, 1 1 ' SH SH CONH, £ O i GH NH-C- ' ^{, T} HGn ₃ N-NH-β-NHCH The compounds of the present invention may be prepared by the use of starting compounds replaced. 11. A process according to claim 4, 28, 53 or 72, for the preparation of compounds of formula II, III or IV, in which R4 is methyl, correspondingly substituted starting compounds are used. 111. - Process according to claim 4, 28, 53 or 72, for the preparation of compounds of formula I, II, III or IV, wherein represents a group -CH ₂ "CH ₂ -, wherein correspondingly substituted starting compounds are used. A method according to claim 4, 28, 53 72, for the preparation of compounds of general formula I, II, III or IV, wherein X is -COREL, wherein the starting materials are the correspondingly substituted. 113. A process according to claim 4, 28, 53 or 72 for the preparation of compounds of general formula I, II, III or IV, wherein X and carbonyl radical groups whose positions in the nucleus may vary, are located at the 3-position of the pyridinium or dihydropyridine nuclei, position 3 of the quinolinium or dihydroquinoline cyclic systems or in the 4-position of the cyclic isoquinolinium or dihydroisoquinolinium systems, characterized in that correspondingly substituted starting compounds are used. 114. The process of claim 4, 28, 53 or 72, for the preparation of compounds of general formula I, II, III or IV, wherein the portion. vehicle is a radical of formula (a) or ^(1), characterized in that use compounds ini- correspondingly substituted initials. 115. A method according to claim 114, for preparation of compounds of general formula I, III or IV, wherein the carrier moiety is a radical of formula characterized in that correspondingly substituted starting compounds are used. 116. A method according to claim 9, 335 5θ or 77? for the preparation of compounds of the general formula 1, II, III or IV, wherein R _y is a methyl group, characterized in that correspondingly substituted starting compounds are used. A process according to claim 9, 33, 5 or 77, for the preparation of compounds of formula I, II, III or IV, wherein X and groups containing carbonyl radicals, whose position in the nucleus may be located at the 3-position of the pyrimidinium or pyrimidiridinium nuclei, at the 3-position of the quinolinium or dihydroquinoline cyclic systems or at the 4-position of the cyclic isoquinolinium or dihydroisoquinolinic systems, characterized in that correspondingly substituted starting compounds . 115. A method according to claim 9 wherein: 33 ' 5% or 77% for the preparation of compounds of general formula I, II, III or IV, wherein R is hydrogen, C1-6 alkyl, cycloalkyl, haloalkyl, furyl or phenyl, characterized in that correspondingly substituted starting compounds are used. 119. A process according to claim 14, 38, 63 or 82, for the preparation of compounds of formula I, II, III or IV, wherein Z 'is an alkylene group of ca linear or branched chain alkyl group, characterized in that correspondingly substituted starting compounds are used. 120. A process according to claim 119, for the preparation of compounds of general formula I, II, III or IV, wherein Z 'is a straight-chain or branched C ₁ -C ₃ -alkylene group, characterized in that the starting materials are the correspondingly unsubstituted. A process according to claim 14, 3θ ' 63 or 82, for the preparation of compounds of formula I, II, III or IV, wherein X and carbonyl radical groups whose positions in the nucleus may vary are located at the 3-position of the pyridinium or dihydropyridine nuclei in position 3 of the quinolinium or dihydroquinolinic cyclic systems or ns. position 4 of the cyclic isoquinolinium or dihydroisoquinolinic systems, characterized in that correspondingly substituted starting compounds are used. 122. - Process according to the. claim 15? 39? 64 or 83, for the preparation of compounds of formula I, II, III or IV, wherein the groups containing carbonyl radicals encompassed by the definitions of R 1 and R 2 are located at the 3-position of the pyridinium or dihydropyridine nuclei , in position 3 of the quinolinium or dihydroquinoline cyclic systems or in the 4-position of the cyclic isoquinolinium or dihydroisoquinolinium systems, characterized in that initial compounds 28: correspondingly substituted. A kit for the preparation of an injectable radioactive drug comprising: (1) a compound of the general formula II defined in claim 25; (2) a pharmaceutically acceptable reducing agent capable of reducing a radioactive metal. to an oxidation state wherein said metal is capable of forming a complex with said compound of formula II; e ') a sterile, biologically compatible aqueous medium. 124. A kit for the preparation of an injectable radioactive drug characterized in that it contains, in separate containers: (1) a salt of general formula I as defined in claim 1; (2) a pharmaceutically acceptable reducing agent, reducing said salt to give the corresponding compound of formula TT in which R 1 and R 2 have the meaning defined in claim 1 and [wherein R 2 represents the reduced biooxidizable formula which penetrates the blood-brain barrier of a dihydropyridines redox vehicle, pyridinium salt, said reducing agent also being capable of reducing a radioactive metal to an oxidation state wherein said metal is capable of forming a complex with said compound of formula 286 general II; and (3) a biologically compatible sterile aqueous medium. A kit according to claim 124, in that technetium is used as the radiating metal which said reducing agent is capable of reducing. characterizes or active A kit as claimed in claim 1 for use as a sodium nitrite agent. 124, characterization, the ditio · A kit according to claim 124, characterized in that an alkaline pH aqueous medium is used. A kit for the preparation of an injectable radioactive drug comprising in separate containers: (1) a salt of the general formula I defined in claim 1 in a sterile, biologically compatible aqueous medium; and (2) a pharmaceutically acceptable reducing agent, reducing said salt to afford the corresponding compound of formula [DHG 7. II in which θ-θ and y have the meaning defined in claim 1 and [-H] represents the reduced biooxidizable form penetrating the blood-brain barrier of a dihydropyridine pyridium salt redox vehicle, said reducing agent being also capable of reducing a me ί ί ί ί ί ί θ θ θ θ θ θ θ such a radioactive to an oxidation state wherein said metal is capable of forming a complex with said compound of formula II. A kit according to claim 126, characterized in that technetium is used as the radioactive metal which the reducing agent mentioned is capable of reducing. 130. A kit according to claim 128, characterized in that the sodium dithionite is used as the reducing agent. A kit according to claim 128, characterized in that an aqueous medium of approximately neutral pH is used. A kit according to claim 128, characterized in that (2) contains a base in addition to said reducing agent. Process for the preparation of radioactive drug compositions, characterized in that: (1) the chelating agent moiety containing at least one functional amino, carboxyl, hydroxy, amide or imide functional group, said functional group not being essential for the complexing properties of said chelating agent, the remainder quot; quot; quot; quot; in the absence of a hydrogen atom of at least one of said reactive functional groups of said chelating agent, said chelating agent being either (a) capable of forming a complex with a radioactive metal isotope or (b) complexed with radioactive metal isotope; and (2) a dihydropyridine pyridinium salt redox vehicle, said remainder of the chelating agent and said vehicle being associated with one another to form a hydrolytically linked ( 282 A process for the preparation of compounds for the on-site supply of radioisotopes and chelating agents usable in their preparation. A process for the preparation of salts of general formula Qhxi ^ ¹¹ characterized in that - reacting a chelating agent or a protected derivative thereof comprising at least one reactive functional group selected from the group consisting of amino, carboxy, hydroxy, amide and imide, said functional group being not essential for the complexing properties of said compound chelating agent, with a reagent capable of substituting a hydrogen atom of at least one of said reactive functional groups by a £ * radical QC ⁺ 3, or R ° ^R capable of being quaternized moiety to provide a moiety [QC ^+] ; quaternized thereafter, when said hydrogen atom has been replaced by a radical capable of providing a radical £ q C ⁺ J; and then, - when the said protected derivative has been used as the starting compound, the protecting group (s) has been removed to give the corresponding salt of formula I. A redox delivery system is also chemical, of the dihydropyridine type >> pyridinium salt for the localized and / or increased site of a radioactive isotope to the brain. A chelating agent capable of forming a complex with a radioactive isotope and carrying a hydroxy, carboxyl, amino, amide or imide reactive group is associated with a carrier group containing a dihydropyridine pyridinium salt nucleus and then complexed with a radioactive isotope to provide a novel radioactive drug which in its lipoidal dihydropyridine form penetrates the blood-brain barrier (" BSC ") and enables increased levels of radioisotope concentration in the brain to be obtained, in particular because the oxidation of the dihydropyridine vehicle group in vivo to provide the ionic pyridinium salt retards elimination from the brain while acceleration is eliminated from the general circulation. This radioisotope delivery system is perfectly adapted for use in scintigraphy and similar radiographic techniques.