US2003027743A1PendingUtilityA1
Tripeptidylpeptidase inhibitors
Est. expiryMay 9, 2015(expired)· nominal 20-yr term from priority
Inventors:Christiane RoseFroylan VargasPierre BourgeatJean-Charles SchwartzPaul Beaumont BishopRamesh B. BambalCharon R. GanellinBertrand LeblondAndrew N. J. MooreLihua ZhaoSuzanne Chan
A61P 3/04A61P 25/18A61P 25/00A61P 25/16A61P 25/24A61P 3/00C07K 5/06052G01N 2333/595C07K 5/06026C12Q 1/37A61K 38/00C07K 5/06191C07D 209/42A61P 21/00A61P 1/00
38
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Claims
Abstract
A compound of the formula wherein the substituents are defined as in the specification and salts or hydrates thereof is disclosed as well as a method of treating disorders associated with the inactivation or excessive degradation of cholecystokinin.
Claims
exact text as granted — not AI-modified1 . Process for screening drugs intended for treating, in man or animals, disorders or complaints associated with the inactivation or excessive degradation (or which may be treated by delaying the physiological degradation), of endogenous neuropeptides, wherein it consists in placing a candidate molecule in contact with a membrane-bound tripeptidylpeptidase or homologue and in measuring the activity of this enzyme.
2 . Process according to claim 1 , wherein the tripeptidylpeptidase is prepared according to the process comprising the following steps:
i) preparation of membranes from brain, for example from rat brain; ii) purification by high performance liquid chromatography/ies (HPLC); iii) checking of the product obtained, by enzymatic reaction using a CCK substrate, for example CCK-5 or (non-sulphated) CCK-8 peptides.
3 . Process according to claim 1 , wherein the tripeptidylpeptidase corresponds to the sequence identity SEQ ID No. 1 of the appended sequence listing.
4 . Process according to claim 1 , wherein the tripeptidylpeptidase corresponds to the sequence identity SEQ ID No. 2 of the appended sequence listing.
5 . Process according to claim 1 , wherein it comprises incubating membranes from brain, for example from rat brain, prepared by centrifugation of a homogenate, in the presence of an aminotripeptidylpeptidase substrate and a candidate molecule, which is a potential inhibitor of the enzymatic activity.
6 . Process according to claim 1 , wherein the disorders or complaints are associated with the inactivation of cholecystokinin (CCK).
7 . Compound of general formula (I) below:
in which:
R 1 represents a hydrogen or a linear or branched C 1 -C 4 alkyl group;
R 2 represents a hydrogen or a C 1 -C 2 alkyl group;
at least one from among R 1 and R 2 representing a hydrogen;
n=0 or 1 and m=0 or 1 with n being different from m;
R and R′ each independently represent a hydrogen or a C 1 -C 2 alkyl group;
R 3 represents a divalent radical consisting of a —(CH 2 ) 2 —, —CH 2 —CH(cis.F)— or —CH 2 —CH(CH 2 Ph)— alkyl chain, of a unit
where R 6 represents H, F, OCH 3 or OCH 2 Ph, where R 8 , R 9 and R 10 each represent a hydrogen or halogen atom, an O(C 1 -C 4 alkyl), OCH 2 Ph, OH or C 1 -C 4 alkyl group, including R 6 , (m) and (n) indicating the bond orientation with respect to the (CH 2 ) n group (or to N if n=0) and to the (CRR′) m group (or to CHR 4 if m=0);
R 4 represents an amide group CO—NH—R 5 where R 5 represents a hydrogen or a linear or branched C 1 -C 6 alkyl, —(CH 2 ) 3 —SCH 3 , —CH 2 Ph, —CH 2 C 6 H 11 , (CH 2 ) 3 OH,
group, as well as the corresponding salts or hydrates thereof, with the proviso that when R 2 , R and R′ represent a hydrogen, R 3 represents the divalent radical —(CH 2 ) 2 —, n=0 and m=1 or n=1 and m=0 and R 4 represents the amide group CO—NH—R 5 , then R 1 is other than CH 2 CH 3 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH 3 when R 5 is a hydrogen, R 1 is other than CH 2 CH(CH 3 ) 2 when R 5 is the CH 2 CH 3 group and R 1 is other than CH 3 when R 5 is the —(CH 2 ) 4 —CH 3 , —CH(CH 3 ) 2 CH 2 CH 3 or CH 3 group or a hydrogen atom, or the unit
8 . Compound according to claim 7 , of general formula (I′) below:
in which:
R 1 represents a hydrogen or a linear or branched C 1 -C 4 alkyl group;
R 2 represents a hydrogen or a C 1 -C 2 alkyl group;
at least one from among R 1 and R 2 representing a hydrogen;
n=0 or 1 and m=0 or 1 with n being different from m;
R 3 represents a divalent radical consisting of a —(CH 2 ) 2 —, —CH 2 —CH(cis.F)— or —CH 2 —CH(CH 2 Ph)— alkyl chain, of a unit
where R 6 represents H, F, OCH 3 or OCH 2 Ph,
R 4 represents an amide group CO—NH—R 5 where R 5 represents a hydrogen or a linear or branched C 1 -C 6 alkyl, —(CH 2 ) 3 —SCH 3 , —CH 2 Ph, —CH 2 C 6 H 11 ,
group.
9 . Compound according to claim 7 , wherein R 3 represents —(CH 2 ) 2 —.
10 . Compound according to claim 7 , wherein R 3 represents —CH 2 —CH (cis.F)—.
11 . Compound according to claim 7 , wherein R 3 represents —CH 2 —CH(CH 2 Ph)—.
12 . Compound according to claim 7 , wherein n=0 and m=1.
13 . Compound according to claim 12 , wherein R 3 represents
14 . Compound according to claim 12 , wherein R and R′ represent a hydrogen and R 3 represents
15 . Compound according to claim 12 , wherein R 3 represents
16 . Compound according to claim 12 , wherein R 3 represents the unit
17 . Compound according to claim 7 , wherein n=1 and m=0.
18 . Compound according to claim 17 , wherein R 3 represents
19 . Compound according to claim 7 , wherein R 5 represents the n-butyl group.
20 . Compound according to claim 7 , wherein R 2 represents a hydrogen.
21 . Compound according to claim 7 , wherein R 1 represents a hydrogen.
22 . Compound according to claim 7 , wherein it is chosen from the group comprising:
L-valyl-L-proline n-hexylamide; 1-(2(S)-aminobutyryl)-L-proline 3-(methylthio)propylamide; 1-(2(S)-aminobutyryl)-L-proline n-pentylamide; 1-(2(S)-aminobutyryl)-L-proline n-butylamide; 1-(2(S)-aminobutyryl)-L-proline [2(S)-methyl]butylamide; 1-(2(S)-aminobutyryl)-L-proline n-propylamide; 1-(2(S)-aminobutyryl)-L-proline iso-butylamide; L-valyl-L-proline n-butylamide; L-alanyl-L-prolyldifluoro-L-borovaline borohydride; 1-(2(S)-aminobutyryl)-(4(S)-fluoro)-L-proline n-butylamide; 1-(2(S)-aminobutyryl)-(4(S)-benzyl)-L-proline n-butylamide; 2-(2(S)-aminobutyryl)-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid n-butylamide; 1-(2(S)-aminobutyryl)-2(S)-indolinecarboxylic acid n-butylamide; 1-(2(S)-aminobutyryl)-2(S)-indolinecarboxylic acid n-propylamide; 1-(2(S)-aminobutyryl)-2(S)-indolinecarboxylic acid methylamide; 1-(2(S)-aminobutyryl)-2(S)-indolinecarboxylic acid ethylamide; 1-(2(S)-aminobutyryl)-2(R/S)-(5-methoxy)indolinecarboxylic acid n-butylamide; 1-(2(S)-aminobutyryl)-2(R/S)-(6-methoxy)indolinecarboxylic acid n-butylamide; 1-(2(S)-aminobutyryl)-2(R/S)-(5-fluoro)indolinecarboxylic acid n-butylamide; 1-(2(S)-aminobutyryl)-2(R/S)-(5-benzyloxy)indolinecarboxylic acid n-butylamide; 1-(2(S)-aminobutyryl)-2(S)-[(3aS, 7aS)-perhydro]indolinecarboxylic acid n-butylamide; 2-(2 (S)-aminobutyryl)-1(R/S)isoindolinecarboxylic acid n-butylamide; as well as the corresponding salts or hydrates thereof.
23 . Compound according to claim 14 , wherein it is chosen from the group comprising:
1-(2(S)-aminobutyryl)-2(S)-indolinecarboxylic acid n-butylamide; 1-(2(S)-aminobutyryl)-2(S)-indolinecarboxylic acid n-propylamide; acid n-propylamide; 1-(2(S)-aminobutyryl)-2(S)-indolinecarboxylic acid ethylamide; 1-(2(S)-aminobutyryl)-2(R/S)-(5-methoxy)indolinecarboxylic acid n-butylamide; 1-(2(S)-aminobutyryl)-2(R/S)-(5-fluoro)indolinecarboxylic acid n-butylamide; as well as the corresponding salts or hydrates thereof
24 . Compound according to claim 16 , wherein it is chosen from the group comprising:
1-(L-valyl)-5-methoxyindoline-2(R/S)-carboxylic acid butylamide; 1-(L-alanyl)-5-methoxyindoline-2(R/S)-carboxylic acid butylamide; 1-(L-alanyl)-5-methoxyindoline-2(S)-carboxylic acid butylamide; 1-(2(S)-aminobutyryl)-4-methoxyindoline-2(R/S)-carboxylic acid butylamide; 1-(2(S)-aminobutyryl)-3,3-dimethylindoline-2(R/S)-carboxylic acid butylamide; 1-(2(S)-aminobutyryl)-3(R)-methylindoline-2(R)-carboxylic acid butylamide and 1-(2(S)-aminobutyryl)-2(S)-methylindoline-2(S)-carboxylic acid butylamide; 1-(2(S)-aminobutyryl)-3(R)-methylindoline-2(S)-carboxylic acid butylamide and 1-(2(S)-aminobutyryl)-3(S)-methylindoline-2(R)-carboxylic acid butylamide; 1-(2(S)-aminobutyryl)-4-ethoxyindoline-2(S)-carboxylic acid butylamide; p 0 1-(2(S)-aminobutyryl)-4,5-dimethoxyindoline-2(R/S)-carboxylic acid butylamide; 1-(2 (S)-aminobutyryl)-5-hydroxyindoline-2 (S)-carboxylic acid butylamide; p 0 1-(2(S)-aminobutyryl)-5-hydroxy-indoline-2(R/S)-carboxylic acid butylamide; p 0 1-(2(S)-aminobutyryl)-5-methylindoline-2(R/S)-carboxylic acid butylamide; 1-(2(S)-aminobutyryl)-5-chloroindoline-2(S)-carboxylic acid butylamide; 1-(2(S)-aminobutyryl)indoline-2(S)-carboxylic acid (3-hydroxy)propylamide; as well as the corresponding salts or hydrates thereof.
25 . Process for the preparation of a compound of general formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 represents a hydrogen; n=0 or 1 and m=0 or 1 with n being different from m and R 3 represents —(CH 2 ) 2 —; and R and R′ represent a hydrogen; R 4 represents CO—NH—R 5 ,
in which R 5 represents a hydrogen or a linear or branched C 1 -C 6 alkyl, —(CH 2 ) 3 —S—CH 3 or —CH 2 Ph group;
wherein it comprises:
i) the formation of a compound of formula (III)
in which R 1 and R 2 have the meanings given above and X represents a protecting group, starting with a compound of formula (II) which is esterified on its acid function with a group Y and in which X, R 1 and R 2 have the meanings given above, by reaction with L-proline;
(ii) amidation of the acid function of compound (III) with the appropriate amine R 5 NH 2 where R 5 has the meaning given above, in order to form the derivative (IV)
which is protected on its primary amine function with the group X;
iii) removal of the group X from the derivative (IV), in order to obtain the desired compound (I).
26 . Process for the preparation of a compound of general formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 represents a hydrogen or a methyl group; n=0 or 1 and m=0 or 1 with n being different from m, and R 3 represents a —(CH 2 ) 2 — group; and R and R′ represent a hydrogen; R 4 represents a group CO—NH—R 5 in which R 5 represents a hydrogen or a linear or branched C 1 -C 6 alkyl group; wherein it comprises:
i) formation of a compound of formula (IV)
in which R 1 , R 2 and R 5 have the meanings given above and X represents a protecting group, starting with a compound of formula (II) which is esterified on its acid function with a group Y and in which R 1 , R 2 and X have the meanings given above, by reaction with a prolineamide of formula (V) in which R 5 has the meaning given above;
ii) removal of the protecting group X from compound (IV) in order to obtain the desired compound (I).
27 . Process for the preparation of a compound of general formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 represents a hydrogen; n=0 and m=1 and R 3 represents a group R and R′ represent a hydrogen; R 4 represents a group CO—NH—R 5 in which R 5 represents a hydrogen or a linear or branched C 1 -C 6 alkyl group; wherein it comprises:
i) preparation of a compound of formula (X)
in which R 1 , R 2 , R 3 and R 4 have the meanings given above and X represents a protecting group, by reaction of a compound of formula (VIII) with a compound of formula (IX) in which R 1 , R 2 , R 4 and X have the meanings given above;
ii) removal of the group X from the compound (X), in order to form the desired compound (I).
28 . Process for the preparation of a compound of general formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 represents a hydrogen; n=1 and m=0 and R 3 represents a —CH(CH 2 Ph)—CH 2 — group or R 4 represents an amide group CO—NH—R 5 in which R 5 represents a hydrogen or a linear or branched C 1 -C 6 alkyl group; wherein it comprises:
i) production of a compound (XII)
which is protected on its primary amine function with a protecting group X and in which R 1 , R 2 and R 3 have the meanings given above, by reaction of the compound of formula (IX) with the compound of formula (XI) in which R 1 , R 2 and R 3 have the meanings given above and X represents a protecting group;
ii) hydrolysis of the ester function of compound (XII) thus obtained, in order to form the compound of formula (XIII)
in which R 1 , R 2 , R 3 and X have the meanings given above;
iii) amidation of the acid function of compound (XIII) using the appropriate amine R 5 NH 2 , in order to form the derivative of formula (XIV)
in which R 1 , R 2 , R 3 , R 5 and X have the meanings given above;
iv) removal of the protecting group X from the compound (XIV) in order to form the desired compound (I).
29 . Process for the preparation of a compound of general formula (I) given above, in which:
R 1 represents a methyl group; R 2 represents a hydrogen; n=0 or 1 and m=0 or 1 with n being different from m, and R 3 represents the —(CH 2 ) 2 — group; and R 4 represents an amide group CO—NH—R 5 in which R 5 represents the unit R and R′ represent a hydrogen; wherein it comprises:
i) amidation of the acid function of the compound of formula (XIX)
which is protected on its primary amine function with a protecting group X and in which R 1 and R 2 have the meanings given above, using the amine (XVIII) in order to form the derivative (XX) in which R 1 , R 2 , R 5 and X have the meanings given above;
ii) removal of the protecting group X from compound (XX) in order to obtain the desired compound (I).
30 . Process for the preparation of a compound of general formula (I) given above, in which:
R 1 represents a methyl group; R 2 represents a hydrogen; n=0 or 1 and m=0 or 1 with n being different from m, and R 3 represents a —(CH 2 ) 2 — group; and R and R′ represent a hydrogen; R 4 represents a group CO—NH—R 5 in which R 5 represents (CH 3 ) 2 —CH—BF 2 ; wherein it comprises:
i) removal of the pinane unit from the compound of formula (I) in which R 1 , R 2 , n, m, R 3 and R 4 have the meanings given above and R 5 represents
by the action of boron trichloride in methylene chloride, followed by hydrolysis, in order to obtain derivative (XXI)
ii) reaction of compound (XXI) with hydrofluoric acid in order to form the desired compound (I).
31 . Process for the preparation of a compound of general formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 represents a hydrogen; n=0 and m=1 and R 3 represents the unit in which R 6 represents an OCH 3 , OCH 2 Ph or F group; and R and R′ represent a hydrogen; R 4 represents a group CO—NH—R 5 in which R 5 represents a linear or branched C 1 -C 6 alkyl group; wherein it comprises:
i) formation of the amide of formula (XXXXIV)
starting with the ester of formula (XXXXIII)
in which formulae R 6 has the meaning given above, by reaction with the appropriate amine R 5 NH 2 ;
ii) reaction of compound (XXXXIV) with the compound of formula (IX)
in which R 1 and R 2 have the abovementioned meanings and X represents a protecting group, in order to form the compound of formula (XXXXV) in which R 1 , R 2 , R 5 , R 6 and X have the meanings given above;
iii) removal of the group X in order to form the desired compound (I).
32 . Process according to claim 31 , wherein the methyl ester (XXXXIII) is prepared
i) by the action of sodium nitrite in the presence of hydrochloric acid, on the compound of formula (XXXIX) in order to form the compound of formula (XXXX) in which formulae R 6 has the meaning indicated above ii) by addition of ethyl 2-methylacetoacetate to compound (XXXX) thus obtained, in the presence of sodium nitrite in ethanol, in order to form the compound of formula (XXXXI) in which R 6 has the abovementioned meaning; iii) by cyclization in acidic medium, in order to form the ethyl ester (XXXXII) iv) by exchange starting with the ethyl ester (XXXXII) thus obtained, in the presence of magnesium in methanol.
33 . Process for the preparation of a compound of general formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 , R and R′ each represent a hydrogen; n=0 and m=1, and R 3 represents the unit in which R 8 and R 10 represent a hydrogen and R 9 represents a group O(C 1 -C 4 alkyl) or C 1 -C 4 alkyl R 4 represents an amide group CO—NH—R 5 in which R 5 represents a linear or branched C 1 -C 6 alkyl group; wherein it comprises:
i) formation of the amide of formula (49)
starting with the ester of formula (48)
in which R 9 and R 5 have the meaning given above, by reaction with the appropriate amine R 5 NH 2 ;
ii) reaction of compound (49) with the compound of formula (IX)
in which R 1 and P 2 have the abovementioned meanings and X represents a protecting group, in order to form the compound of formula (50) in which R 1 , R 2 , R 9 and X have the meanings given above;
iii) removal of the group X in order to form the desired compound (I).
34 . Process according to claim 33 , wherein the methyl ester (48) is obtained from the corresponding acid (46)
in which R 9 has the meaning given above
i) by treatment in ethanol or methanol with concentrated sulphuric acid, in order to lead to the corresponding ester (47)
in which R 9 is as defined above
ii) after which, compound (47) is treated with magnesium in methanol.
35 . Process for the preparation of a compound of general formula (I) given above, in which
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 , R and R′ each represent a hydrogen; n=0 and m=1, and R 3 represents the unit in which R 8 and R 9 represent a hydrogen or an O(C 1 -C 4 alkyl) group, it not being possible for R 8 and R 9 simultaneously to represent a hydrogen, and R 10 represents a hydrogen R 4 represents an amide group CONHR 5 in which R 5 is a linear or branched C 1 -C 6 alkyl group, wherein it comprises:
i) formation of compound (54)
by reaction of the corresponding aldehyde (53)
in which R 8 , R 9 and R 10 are as defined above with ethyl azidoacetate (52)
ii) cyclization of compound (54) in order to lead to compound (55)
in which R 8 , R 9 and R 10 have the meanings given above
iii) formation of methyl ester (56)
in which R 8 , R 9 and R 10 have the meanings given above starting with compound (55) in the presence of magnesium in methanol
iv) reaction of the ester (56) obtained with the appropriate amine R 5 NH 2 in order to form the amide (57)
in which R 8 , R 9 and R 10 are as defined above
v) reaction of compound (57) with the compound of formula (IX)
in which R 1 and R 2 have the abovementioned meaning and X represents a protecting group, in order to form compound (58) in which R 1 , R 2 , R 5 , R 8 , R 9 , R 10 and X have the meaning given above,
vi) removal of the group X in order to form the desired compound (I).
36 . Process for the preparation of a compound of formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 represents a hydrogen; one of the substituents R or R′ represents a hydrogen and the other a C 1 -C 2 alkyl group; n=0 and m=1 and R 3 represents the unit with R 8 , R 9 and R 10 representing a hydrogen R 4 represents an amide group CONHR 5 in which R 5 is a linear or branched C 1 -C 6 alkyl group, wherein it comprises:
i) formation of compound (59)
in which P and R′ are as defined above by reaction between phenylhydrazine and 2-ketobutyric acid in acidic medium
ii) formation of compound (60) from the compound (59) obtained
in which P and P′ are as defined above in the presence of magnesium in methanol,
iii) formation of the amide (61) corresponding to compound (60) by reaction with the appropriate amine R 5 NH 2
in which R and R′ are as defined above
iv) separation of the cis isomers (61a), on the one hand, and the trans isomers (61b), on the other hand, of compound (61)
v) reaction, respectively, of compounds (61a) and (61b) with compound (IX)
in which R 1 and R 2 have the meaning given above and X represents a protecting group, in order to form mixtures (62a) and (62b) respectively
in which R 1 , R 2 , R, R′ and R 5 have the meaning given above
vi) removal of the protecting group X, leading to the desired compound (I) in the form of cis pairs (63a) and trans pairs (63b), respectively.
37 . Process for the preparation of a compound of formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 represents a hydrogen; R and R′ each represent a C 1 -C 2 alkyl group, which may be identical or different; n=0 and m=1 and R 3 represents the unit in which R 8 , R 9 and R 10 each represent a hydrogen; R 4 represents an amide group CONHR 5 in which R 5 is a linear or branched C 1 -C 6 alkyl group; wherein it comprises:
i) formation of compound (65) of the following formula:
by reaction of phenylhydrazine with a compound
ii) cyclization of compound (65) in acidic medium, in order to form compound (66) below:
in which R and R′ are as defined above
iii) hydrogenation of compound (66), leading to compound (67) below
in which R and R′ are as defined above
iv) formation of the corresponding amide (68) by the action of LiNHR 5 in which R 5 has the abovementioned meaning
in which R and R′ are as defined above
v) reaction of compound (68) with the compound of formula (IX)
in which R 1 and R 2 have the meaning given above and X is a protecting group, in order to form compound (69)
in which R and R′ are as defined above
vi) removal of the group X in order to form the desired compound (I).
38 . Process for the preparation of a compound of formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 , R and R′ each represent a hydrogen; n=0 and m=1, and R 3 represents the unit in which R 9 represents an OH group and R 8 and R 10 both represent a hydrogen; R 4 represents an amide group CONHR 5 in which R 5 is a linear or branched C 1 -C 6 alkyl group; wherein it comprises:
i) formation of compound (71)
in which R 9 represents an OCH 2 Ph group, R 5 has the meaning given above and X represents a protecting group, by reaction of compound (70) in which R 5 is as defined above, with a compound (IX) in which R 1 and R 2 have the meaning given above and X represents a protecting group,
ii) removal of the groups CH 2 Ph and X from compound (71) in order to form the desired compound (I).
39 . Process for the preparation of a compound of formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 , R and R′ each represent a hydrogen; n=0 and m=1, and R 3 represents the unit in which R 9 represents a halogen atom and R 8 and R 10 each represent a hydrogen R 4 represents an amide group CONHR 5 in which R 5 is a linear or branched C 1 -C 6 alkyl group; wherein it comprises:
i) formation of the methyl ester (73)
from the corresponding acid (72)
in which R 9 is as defined above, with concentrated sulphuric acid in methanol,
ii) formation of compound (74)
in which R 9 is as defined above, starting with compound (73), with magnesium in methanol,
iii) formation of the corresponding amide (75) by reaction with the appropriate amine R 5 NH 2
in which R 8 and R 9 are as defined above
iv) reaction of compound (75) with a compound (IX)
in which R 1 and R 2 have the meanings given above and X represents a protecting group, in order to form compound (76) in which R 1 , R 2 , R 5 , R 9 and X have the meanings given above,
v) removal of the group X in order to form the desired compound (I).
40 . Process for the preparation of a compound of formula (I) given above, in which:
R 1 represents a linear or branched C 1 -C 4 alkyl group; R 2 , R and R′ each represent a hydrogen; n=0 and m=1, and R 3 represents the unit in which R 8 , R 9 and R 10 each represent a hydrogen; R 4 represents an amide group CONHR 5 in which R 5 is a (CH 2 ) 3 OH group, wherein it comprises:
i) reaction of the methyl ester of indoline-2S-carboxylic acid with a compound of formula (IX)
in which R 1 and R 2 have the meaning given above and X represents a protecting group, in order to form compound (77) below in which R 1 , R 2 and X are as defined above
ii) formation of amide (78)
in which R 1 and R 2 have the above meaning starting with compound (77), by the action of 3-hydroxypropylamine in methanol
iii) removal of the group X in order to form the desired compound (I).
41 . Use of a compound of general formula (I) according to any one of claims 7 to 24 as a drug for the treatment, in man or animals, of disorders or complaints associated with the inactivation or excessive degradation (or which may be treated by delaying the physiological degradation) of endogenous neuropeptides.
42 . Use according to claim 41 , wherein the disorders or complaints are associated with the inactivation of cholecystokinin (CCK).
43 . Use according to claim 42 , wherein the disorders or complaints are eating, mood, cognitive or motor disorders, in particular anorexia, schizophrenia, Parkinson's disease and depression, as well as disorders of gastrointestinal transit such as irritable bowel syndrome, bulimia or pathological obesity conditions.
44 . Use of a compound of general formula (I) below:
in which:
R 1 represents a hydrogen or a linear or branched C 1 -C 4 alkyl group;
R 2 represents a hydrogen or a C 1 -C 2 alkyl group;
at least one from among R 1 and R 2 representing a hydrogen;
n=0 or 1 and m=0 or 1 with n being different from m;
R and R′ each independently represent a hydrogen or a C 1 -C 2 alkyl group;
R 3 represents a divalent radical consisting of a —(CH 2 ) 2 —, —CH 2 —CH(cis.F)— or —CH 2 —CH(CH 2 Ph)— alkyl chain, of a unit
where R 6 represents H, F, OCH 3 or OCH 2 Ph, where R 8 , R 9 and R 10 each represent a hydrogen or halogen atom, an O(C 1 -C 4 alkyl), OCH 2 Ph, OH or C 1 -C 4 alkyl group, including R 6 , (m) and (n) indicating the bond orientation with respect to the (CH 2 ) n group (or to N if n=0) and to the (CRR′) m group (or to CHR 4 if m=0);
R 4 represents an amide group CO—NH—R 5 where R 5 represents a hydrogen or a linear or branched C 1 -C 6 alkyl, —(CH 2 ) 3 —SCH 3 , —CH 2 Ph, —CH 2 C 6 H 11 , (CH 2 ) 3 OH,
group,
for the preparation of a drug intended for the treatment, in man or animals, of disorders or complaints associated with the inactivation or excessive degradation (or which may be treated by delaying the physiological degradation) of endogenous neuropeptides.
45 . Use according to claim 44 , wherein the compound of general formula (I) is as defined according to any one of claims 8 to 24 .
46 . Use according to claim 44 or 45 , wherein the disorders or complaints are associated with the inactivation of cholecystokinin (CCK).
47 . Use according to claim 46 , wherein the disorders or complaints are eating, mood, cognitive or motor disorders, in particular anorexia, schizophrenia, Parkinson's disease and depression, as well as disorders of gastrointestinal transit such as irritable bowel syndrome, bulimia or pathological obesity conditions.
48 . Pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 7 to 24 in a pharmaceutically acceptable excipient.
49 . Pharmaceutical composition according to claim 48 , wherein it comprises a compound according to claim 22 , 23 or 24 .
50 . Use according to claim 44 or 45 , wherein a compound of formula (I) is used in which R 1 represents a CH 2 CH 3 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH 3 group and R 5 is a hydrogen, in which R 1 represents a CH 2 CH(CH 3 ) 2 group and R 5 represents CH 2 CH 3 , or in which R 1 represents a CH 3 group and R 5 represents the unit
R 2 , R and R′ representing hydrogen, R 3 representing the divalent radical —(CH 2 ) 2 — and R 4 representing the amide group CO—NH—R 5 .Join the waitlist — get patent alerts
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