WO1993013072A1 - 5-isoquinolinesulfonamide derivatives as protein kinase inhibiting agents - Google Patents

5-isoquinolinesulfonamide derivatives as protein kinase inhibiting agents Download PDF

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WO1993013072A1
WO1993013072A1 PCT/EP1992/002869 EP9202869W WO9313072A1 WO 1993013072 A1 WO1993013072 A1 WO 1993013072A1 EP 9202869 W EP9202869 W EP 9202869W WO 9313072 A1 WO9313072 A1 WO 9313072A1
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group
optionally substituted
alkyl
alkylamino
carboxyl
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PCT/EP1992/002869
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French (fr)
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Silvio Levi
Gianni Gromo
Tiziana Maoret
Alberto Sala
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Italfarmaco S.P.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

  • the present invention relates to 5-isoguinoline- sulfonamide derivatives useful as protein kinase inhibiting agents.
  • Protein kinases are enzymes which, through a phosphorilation process, play an important role in transducing extracellular signals responsible of many cell functions, such as proliferation control [Shenolikar S., FASEB J., 2 , 2753 (1988)]. Particularly, it has been demonstrated that some protein kinases are involved in some tumoral etiopathologies [Nishizuka Y., Science, 233, p. 305 (1986)], in inflammatory processes [Ohnori K. et al., Arzneim. Forsch./Drug Res., 38, p. 809 (1988)] and in the activation of the immune system [Alexander D.R: et al., Immun. Today, 10, p. 200 (1989)]. These characteristics make protein kinases very interesting biological structures.
  • the present invention relates
  • R is the group -N-R 3 -N- , wherein R 1 and R 2 are
  • R 3 is straight or branched (C 2 - C 6 ) alkylene, optionally substituted by benzyl or benzyl substituted by at least one substituent selected from the group consisting of C 1 -C 8 alkyl, halogen , hydroxy , C 1 -C 6 alkoxy, nitro, amino , C 1 -C 6 alkylamino di-C 1 -C 6 alkylamino, aliphatic C 2 -C 6 acylamino, C 1 -C 6 carboxyamido, carbonyl, carboxyl, esterified carboxyl, cyano, methylenedioxy, and R 3 is straight or branched (C 2 - C 6 ) alkylene, optionally substituted by benzyl or benzyl substituted by at least one substituent selected from the group consisting of C 1 -C 8 alkyl, halogen, hydroxy, C 1 -C 6 alkoxy, nitro, amino, C 1 -C 6 alky
  • the compounds of formula I are prepared with a process comprising the reaction between an amine of formula II or II'
  • R 1 , R 2 and R 3 are as above defined , a and b are independently methylene , ethylene or propylene , optionally substituted by at least one C 1 -C 4 alkyl group, alo is a halogen atom , preferably chlorine or bromine and X is as above defined, optionally in the form of an inorganic or organic salt.
  • the conditions of the reaction between the diamine of formula II or II' and the sulfonyl chloride of formula III can vary according to the fact whether the two diamino nitrogen atoms have the same or different nucleophilicity and X be or not different from 5-isoquinolyl.
  • the reaction occurs in a single step, by reacting a molar amount of the amine II or II' with at least a twice molar amount of the sulfonyl chloride of formula III. This last is gradually added to the reaction mixture containing the diamine, which is dissolved into an appropriate organic solvent, such as for example a halogenated aliphatic hydrocarbon, tetrahydrofurane, dioxane, acetone, toluene or their mixtures, and a tertiary aliphatic or aromatic amine, such as for example triethylamine, which acts as acidity acceptor.
  • an appropriate organic solvent such as for example a halogenated aliphatic hydrocarbon, tetrahydrofurane, dioxane, acetone, toluene or their mixtures, and a tertiary aliphatic or aromatic amine, such as for example triethylamine, which acts as acidity acceptor.
  • DMAP N,N-dimethyl-4-aminopyridine
  • alo is as above defined, in substantially analogous conditions as the ones above described.
  • the protection is carried out by the techniques well known to the expert in the field.
  • Appropriate protecting groups which however must be such as to be easily removed, are for example t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Aloe) and the like. Said protection is carried out according to the normal procedures well known in the art (T.W. Greene and P.G.M. Wuts - "Protective groups in organic synthesis", 2nd ed., J. Wiley & Son, 1991).
  • the diamine of formula II or II' is subsequently reacted with the sulphonyl chloride of formula III, where X is different from 5-isoquinolyl, in equimolar amounts and in the substantially same conditions as above described, to give the compound of formula IV.
  • P-R'-SO 2 X IV wherein P is an appropriate protecting group and R' is as above defined for the compound IV.
  • the compound IV which can be whether isolated and characterized or used as such, is subjected to a deprotection reaction according to procedures common to the expert in the field. (T.W. Greene and P.G.M. Wuts supra) to give the compound of formula IV.
  • the reaction between said compound IV and the compound V substantially occurs in the same conditions as above described.
  • N-(5-isoquinolinesulfonyl)-N-methyl-N'-(1-naphthalenesulfonyl)-ethylenediamine hydrochloride A) 2.94 g (0.0135 mol) of diter-butoxy dicarbonate (Boc20) in 10 ml of chloroform were dropped into a solution of 2 g (0.027 mol) of N-methyl-ethylenediamine in 15 ml of chloroform. The mixture was kept at room temperature overnight (about 20 hours), then the solvent was evaporated off. 3.5 g of a crude product were obtained, and it was subsequently purified on a silica gel column by eluting with a 9/1 (v/v) chloroform/methanol mixture. 1.53 g of N'-carbobenzoxy-N'-methyl-ethylenediamine were obtained. (Yield: 65%)
  • the crude product was treated with 5 ml of methanol saturated with HCl at room temperature, giving 1.4 g of crude N-methyl-N'-(1-naphthalene- sulfonyl)-ethylenediamine hydrochloride.
  • N,N'-bis-(5-isoquinolinesulfonyl)-cyclohexylene1,3-diamine - N-phenyl-N,N'-bis-(5-isoquinolinesulfonyl)-ethylenediamine.
  • N,N'-bis-(5-isoquinolinesulfonyl)-N-propyl-ethylenediamine - N,N'-bis-(5-isoquinolinesulfonyl)-N-propyl-ethylenediamine.
  • the compounds of the present invention are active as inhibiting agents of the protein kinases, therefore are partially useful in cardiovascular pathologies, as well as in the inflammatory and immune diseases, in oncology and in organ transplants.
  • the inhibiting activity of the present compounds is illustrated by the following test:
  • Some compounds of the invention have been tested as to the protein kinase A and C inhibiting activity by using partially purified preparates of these enzymes, obtained according to the method of U. Kikkawa et al., Biochem. Bioph. Res. Commun., vol 135, No. 2 (1986).
  • the inhibiting activity of the tested compounds which have been administered at 100 ⁇ M concentration, is expressed as percent of the protein kinase A and C acti vity, the latter being measured by the evaluation of the 32P coming from bovine histon 32P-ATP according to the method described by U. Kikkawa et al., J. Biol. Chem., vol. 257, p. 13341-13345 (1982). The results are shown in Table 1.
  • a further object of the present invention is the use of the new compounds as protein kinase inhibiting agents, with reference to the acts and aspects industrially appilcable of said use, the incorporation thereof in pharmaceutical compositions.
  • the compounds of formula I can be administered appropriately formulated in pharmaceutical compositions, according to what descibed for example in "Remington's Pharmaceutical Sciences Handbook", Mack Pub. Co. XVII ed. N.Y., USA.
  • pharmaceutical compositions are sugar coated pills, capsules, syrups, suppositories, parente rally administrable ampoules, microgranules and the like.
  • the posology will obviously depend on more factors, such as type and gravity of the pathologies to be treated and patient conditions (weight, sex, age, etc.).

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

5-isoquinolinesulfonamide derivatives of formula (I) wherein R is the group α, where R1 and R2 are independently hydrogen, methyl, ethyl, straight or branched C3-C6 alkyl, benzyl, optionally substituted by at least one substituent selected from the group consisting of C1-C8 alkyl, halogen, hydroxy, C1-C6 alkoxy, nitro, amino, C1-C6 alkylamino di-C1-C6 alkylamino, aliphatic C2-C6 acylamino, C1-C6 carboxyamido, carbonyl, carboxyl, esterified carboxyl, cyano, methylenedioxy, and R3 is straight or branched (C2-C6)alkylene, optionally substituted by benzyl or benzyl substituted by at least one substituent selected from the group consisting of C1-C8 alkyl, halogen, hydroxy, C1-C6 alkoxy, nitro, amino, C1-C6 alkylamino di-C1-C6 alkylamino, aliphatic C2-C6 acylamino, C1-C6 carboxyamido, carbonyl, carboxyl, esterified carboxyl, cyano, methylenedioxy or C5-C8 cycloalkylene; or R is the bivalent residue β where a and b are independently methylene, ethylene or propylene, optionally substituted by at least one C1-C4 alkyl group; X is an aromatic, partially or totally hydrogenated isoquinoline group, optionally substituted by at least one C1-C4 alkyl group, or the partially or totally hydrogenated naphthyl group and optionally substituted with at least one C1-C4 alkyl group; the salts with pharmaceutically acceptable acids thereof; said derivatives are useful as protein kinases inhibiting agents.

Description

5-ISOQOINOLINESOLFONAMIDE DERIVATIVES AS PROTEIN KINAS INHIBITING AGENTS
The present invention relates to 5-isoguinoline- sulfonamide derivatives useful as protein kinase inhibiting agents.
Protein kinases are enzymes which, through a phosphorilation process, play an important role in transducing extracellular signals responsible of many cell functions, such as proliferation control [Shenolikar S., FASEB J., 2 , 2753 (1988)]. Particularly, it has been demonstrated that some protein kinases are involved in some tumoral etiopathologies [Nishizuka Y., Science, 233, p. 305 (1986)], in inflammatory processes [Ohnori K. et al., Arzneim. Forsch./Drug Res., 38, p. 809 (1988)] and in the activation of the immune system [Alexander D.R: et al., Immun. Today, 10, p. 200 (1989)]. These characteristics make protein kinases very interesting biological structures.
Hidaka H. et al., Biochemistry, 32, 5036 (1984) describe a class of isoquinolinesuIfonamides having inhibiting activity towards cyclic nucleotide dependent protein kinases (PKA and PKG) and protein kinases C (PKC). The same class is claimed in EP 0061673, which describes said compounds as having cardiovascular activity. An antitumor activity has been suggested for some of these isoquinolinesulfonamides. Particularly, Martell R.E. et al., Biochem. Pharm., 37, 635 (1988) show the effects of two isoquinolinesulfonamides, namely 1- (5-isoquinolinsulfonyl)-2-methylpiperazine (H-7) and N- [2-guanidinoethyl]-5-isoquinolinesulfonamide (HA-1004), which have a certain selectivity for PKC and cyclic nu- cleotide dependent protein kinases , respectively, on the calcitriol-induced cell differentiation . Further, Nishikawa M. et al . , Life Sci. , 39, 1101-1107 (1986 ) , demonstrate that the same H-7 inhibits the cell differentiation induced by forbol diester.
Other classes of compounds well known in the prior art (EP-A-397060 , DE-A-3914764 and EP-A-384349 ) showed the capacity of inhibiting protein kinases , however, said compounds have a chemical structure which is totally different from the one of the compounds of the present invention .
It has now surprisingly been found a class of iso- quinolinesulfonamide derivatives which are protein kinase inhibiting agents. Some of these compounds proved to be selectively active towards a specific type of protein kinases .
More particularly, the present invention relates
-to compounds of the general formula I :
SO2RSO2X
Figure imgf000004_0001
wherein R is the group -N-R3-N- , where R 1 and R2 are
Figure imgf000004_0002
Figure imgf000004_0003
R1 R2
independently hydrogen, methyl, ethyl, straight or branched C3-c6 alkyl, benzyl, optionally substituted by at least one substituent selected from the group consisting of C1-C8 alkyl, halogen , hydroxy , C1-C6 alkoxy, nitro, amino , C1-C6 alkylamino di-C1-C6 alkylamino, aliphatic C2-C6 acylamino, C1-C6 carboxyamido, carbonyl, carboxyl, esterified carboxyl, cyano, methylenedioxy, and R3 is straight or branched (C2- C6) alkylene, optionally substituted by benzyl or benzyl substituted by at least one substituent selected from the group consisting of C1-C8 alkyl, halogen, hydroxy, C1-C6 alkoxy, nitro, amino, C1-C6 alkylamino di-C1-C6 alkylamino, aliphatic C2-C6 acylamino, C1-C6 carboxyamido, carbonyl, carboxyl, esterified carboxyl, cyano, methylenedioxy or C5-C8 cycloalkylene; or R is the bivalent residue of a 4-8 membered heterocyclic group, bound to SO2 groups through nitrogen atoms, optionally substituted by at least one C1-C4 alkyl group; X is an aromatic, partially or totally hydrogenated isoquinoline group, optionally substituted by at least one C1-C4 alkyl group, or the partially or totally hydrogenated naphthyl group and optionally substituted with at least one C1-C4 alkyl group; the salts with pharmaceutically acceptable acids thereof.
The compounds of formula I are prepared with a process comprising the reaction between an amine of formula II or II'
Figure imgf000005_0001
and a sul fonyl chloride of formula II I
alo-SO2X III
In these compounds R1 , R2 and R3 are as above defined , a and b are independently methylene , ethylene or propylene , optionally substituted by at least one C1-C4 alkyl group, alo is a halogen atom , preferably chlorine or bromine and X is as above defined, optionally in the form of an inorganic or organic salt.
The conditions of the reaction between the diamine of formula II or II' and the sulfonyl chloride of formula III can vary according to the fact whether the two diamino nitrogen atoms have the same or different nucleophilicity and X be or not different from 5-isoquinolyl.
Thus, when X is 5-isoquinolyl, the reaction occurs in a single step, by reacting a molar amount of the amine II or II' with at least a twice molar amount of the sulfonyl chloride of formula III. This last is gradually added to the reaction mixture containing the diamine, which is dissolved into an appropriate organic solvent, such as for example a halogenated aliphatic hydrocarbon, tetrahydrofurane, dioxane, acetone, toluene or their mixtures, and a tertiary aliphatic or aromatic amine, such as for example triethylamine, which acts as acidity acceptor. It has also been found that the addition of particular organic bases such as for example N,N-dimethyl-4-aminopyridine (DMAP) helps the reaction progress. The reaction is completed within a period of time comprised between about 10 minutes and 72 hour, and occurs at a temperature from about 10 to about 40°C.
When instead X is a group different from 5-isoquinolyl and in the diamine of formula II or II' the nitrogen atoms have the same nucleophilicity, a molar amount of said diamine is reacted with an equimolar amount of sulphonyl chloride of formula III. The reac tion conditions are substantially the same as those above described. A compound of formula IV is obtained:
HR'SO2X IV
wherein X is as above defined, except 5-isoquinolyl, and R' has the same meanings as R in formula I, with the proviso that when R is -N-R3-N-, R1 is the same as
Figure imgf000007_0002
Figure imgf000007_0003
R1 R2
R2, and when R is the bivalent residue of a heterocyclic group, it can not be substituted. The so obtained compound of formula IV, which can be whether isolated and characterized or used as such for the subsequent step, is treated with at least one molar equivalent of a compound of formula V:
Figure imgf000007_0001
wherein alo is as above defined, in substantially analogous conditions as the ones above described.
Finally, when X is different from 5-isoquinolyl and in the diamine of formula II or II' the nitrogen atoms have different nucleophilicity, it is sometimes necessary the preventive protection of the nitrogen atom having the higher nucleophilicity. Such a protection is necessary when the group SO2X, having X different from 5-isoquinolyl, is to be introduced on the nitrogen atom of the diamine of formula II or II' having the lower nucleophilicity.
The protection is carried out by the techniques well known to the expert in the field. Appropriate protecting groups, which however must be such as to be easily removed, are for example t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Aloe) and the like. Said protection is carried out according to the normal procedures well known in the art (T.W. Greene and P.G.M. Wuts - "Protective groups in organic synthesis", 2nd ed., J. Wiley & Son, 1991).
The diamine of formula II or II' is subsequently reacted with the sulphonyl chloride of formula III, where X is different from 5-isoquinolyl, in equimolar amounts and in the substantially same conditions as above described, to give the compound of formula IV.
P-R'-SO2X IV wherein P is an appropriate protecting group and R' is as above defined for the compound IV. The compound IV, which can be whether isolated and characterized or used as such, is subjected to a deprotection reaction according to procedures common to the expert in the field. (T.W. Greene and P.G.M. Wuts supra) to give the compound of formula IV. The reaction between said compound IV and the compound V substantially occurs in the same conditions as above described.
The above discussed protection is not necessary when the group SO2 is to be introduced on the nitrogen atom of the diamine II or II' having the highest nucleophilicity.
Other obvious methods to prepare the compound I can be used and are comprised in the scope of the present invention.
Melting points have been determined with a Buchi 350 apparatus. 1H-NMR and 13C-NMR have been determined with a VARIAN GEMINI 200 spectrometer.
The following examples further illustrate the invention.
EXAMPLE 1
N-methyl-N,N'-bis-(5-isoquinolinesulfonyl)-ethylene- diamine
10 g (0.04 mol) of 5-isoquinoline sulfonyl chloride hydrochloride were added in small portions to a solution of 1.66 ml (0.019 mol) of N-methylenediamine in 80 ml of methylene chloride and 10.6 ml of triethy- lamine (0.08 mol). The solution was kept at room temperature for 16 hours, then the solvent was evaporated off. 11 g of a crude product were obtained, and it was subsequently purified on a silica gel column by eluting with a 9/1/0.5 (v/v) chloroform/methanol/ammonia mixture. 4 g of the title compound in the form of hydrochloride were obtained.
Melting point > 250°C (methanol)
Elemental analysis:
C H N Cl 5
Theoretical: 47.64 4.19 10 .58 13.39 12 .11 Found: 47.59 4.11 10, .49 13.15 12 .24
1H-NMR (DCl 1N; 200 MHz)
s(1H) 9.83; s(1H) 9.80; t(2H) 8.85; m(5H) 8.73÷8.63; d(1H) 8.54; t(1H) 8.06; t(1H) 8.05; m(4H) 3.11; s(3H) 2.60.
13C-NMR (DCl 1N; 50.3 MHz)
150.51 (2c); 142.14; 141.46; 139.51; 139.23; 137.68; 137.30; 137.15; 135.65; (2c), 135.50; 132.91; (2c),
131.18; (2c), 125.40; 125.15; 51.66; 42.25; 36.21. EXAMPLES 2-5
According to the procedure of example 1 and using the appropriate amine of formula II or II', the following compounds in the form of hydrochloride were obtained.
2. 1,4-bis-(5-isoquinolinsulfonyl)-2-methylpiperazine Yield: 20%; melting point > 250°C
Elemental analysis:
C H N Cl S Theoretical: 49.73 4.35 10.09 12.76 11.54
Found: 49.60 4.33 9.98 12.74 11.60 1H-NMR (DCl 1N; 200 MHz)
s(1H) 9.87; s(1H) 9.85; d(1H) 8.99; m(7H) 8.73÷8.66; t(1H) 8.14; t(1H) 8.11; m(1H) 4.32; m(3H) 3.86÷3.61; dt(1H) 3.39; dd(1H) 2.78; dt(1H) 2.53; d(3H) 1.01.
13C-NMR (DCl 1N; 50.3 MHz)
150.79; 150.74; 143.13 (2c); 140.05; 139.87 137.60; 137.15; 136.00; 135.88; 135.83; 134.38 132.96 (2c); 131.21; 131.13; 125.12; 124.79; 52.57 51.10; 47.53; 41.74; 16.63.
3. N,N'-bis-(5-isoquinolinsulfonyl)-ethylenediamine
Yield: 18%; melting point > 250°C
Elemental analysis:
C H ] N Cl S
Theoretical: 46.61 3.91 10 .87 13.76 12 .44 Found: 46.42 3.96 10 .68 13.77 12 .30 1H-NMR (DCl 1N; 200 MHz)
s(2H) 9.80; d(2H) 8.87; m(6H) 8.74+8.60; t(2H)
8.07; s(4H) 2.92.
13C-NMR (DCl 1N; 50.3 MHz) 150.37 141.64; 139.13; 137.13; 136.86; 135.45; 132.71; 131.11; 124.95; 44.34.
4. N,N'-bis-(5-isoquinolinsulfonyl)-propylenediamine Yield: 25%; melting point > 240°C (dec.)
Elemental analysis:
C H N Cl S Theoretical: 47.64 4.19 10.58 13.39 12.11 Found: 47.51 4.23 10.41 13.21 12.25 1H-NMR (DMSO; 200 MHz)
s(broad, 2H) 10.93; s(2H) 10.04; m(4H) 8.87; d(2H) 8.78; t(2H) 8.54; d(2H) 8.53; t(2H) 8.10; m(4H) 2.73; quintetto (2H) 1.43.
13C-NMR (DMSO; 50.3 MHz)
149.25 (2c); 136.50 (2c); 135.80 (2c); 135.62 (2c); 135.42 (2c); 133.20 (2c); 129.36 (2c); 128.63 (2c); 121.43 (2c); 40.11 (2c); 29.56.
5. N,N'-dimethyl-N,N'-bis-(5-isoquinolinsulfonyl)- ethylenediamine.
Yield: 57%; melting point > 220°C
Elemental analysis:
C H N Cl S Theoretical: 45.70 4.87 9.67 12.24 11.06 Found: 45.83 4.84 9.75 12.22 11.13 1H-NMR (DMSO; 200 MHz)
s(2H) 10.02; m(6H) 8.85÷8.76; d(2H) 8.59; t(2H) 8.11; s(broad, 2H) 7.58; s(4H) 3.38; s(6H) 2.84. 13C-NMR (DMSO; 50.3 MHz)
149.85 (2c); 136.91 (2c); 136.73 (2c); 136.00 (2c); 133.69 (2c); 133.48 (2c); 129.20 (2c); 128.89 (2c); 120.99 (2c); 47.13 (2c); 34.65 (2c).
EXAMPLE 6 N,N'-bis-(5-isoquinolinesulfonyl)-N-isopropylethylene- diamine.
Yield: 39%; melting point > 230°C
Elemental analysis:
C H N Cl S
Theoretical: 49.55 4.70 10.05 12.72 11.50 Found: 49.36 4.62 9.98 12.75 11.57 1H-NMR (DMSO; 200 MHz)
s(1H) 9.94; s(1H) 9.88; m( H) 8.89÷8.68; m(3H) 8.60÷8.49; t(1H) 8.08; t(1H) 8.02; m(1H) 4.05; m(2H) 3.21; m(2H) 2.95; d(6H) 0.93.
13C-NMR (DMSO; 50.3 MHz)
150.98; 150.42; 138.90; 137.72; 136.34; 135.71 (3c); 135.37 (2c); 134.49; 135.52; 128.79 (4c); 120.50; 119.75; 49.64; 43.20; 42.05; 20.97.
EXAMPLE 7
N,N'-bis-(5-isoquinolinesulfonyl)-(1S,2S)-cyclohexylene-1,2-diamine.
Yield: 49%; melting point 190-205°C
Elemental analysis:
C H N Cl S
Theoretical: 50.62 4.60 9.84 12.45 11.26
Found: 50.94 4.66 9.89 12.46 11.16
1H-NMR (DMSO; 200 MHz)
s(2H) 9.92; d(2H) 8.81; m(4H) 8.73÷8.67; d(2H) 8.50; d(2H) 8.12; t(2H) 8.03; m(2H) 2.89; m(4H) 1.40÷1.19; m
1.17÷0.84.
13C-NMR (DMSO; 50.3 MHz)
149.63 (2c);. 136.62 (4c); 136.02 (2c); 135.22 (2c); 132.78 (2c); 128.96 (2c); 128.63 (2c); 121.15 (2c);
55.68 (2c); 31.53 (2c); 23.20 (2c). EXAMPLE 8
N , N ' -bis - ( 5-isoquinolinesul fonyl ) - ( 1R , 2R ) -cyclohexylene-1,2-diamine.
Yield: 40%; melting point 195-220°C
Elemental analysis:
C H N Cl S
Theoretical: 50.62 4.60 9.84 12.45 11.26
Found: 50.80 4.65 9.88 12.41 11.26
1H-NMR (DMSO; 200 MHz)
s(2H) 9.99; s(6H) 8.89÷.8.71; d(2H) 8.53; d(2H) 8.17; t(2H) 8.05; m(2H) 2.89; m(4H) 1.48÷1.19; m(4H)
1.18÷0.78.
13C-NMR (DMSO; 50.3 MHz)
149.11 (2c);136.73 (2c); 136.41 (2c); 135.62 (2c); 135.41 (2c); 133.04 (2c); 129.24 (2c); 128.61 (2c);
121.69 (2c); 55.79 (2c); 34.72 (2c); 23.31 (2c).
EXAMPLE 9
N-benzyl-N,N'-bis-(5-isoquinolinesulfonyl)-ethylenediamine.
Yield: 25%; melting point 198°C
Elemental analysis:
C H N Cl S Theoretical: 53.55 4.33 9.25 11.71 10.59 Found: 53.42 4.37 9.23 11.77 10.65 1H-NMR (DMSO; 200 MHz)
s(1H) 10.02; s(1H) 10.00; M( 8H) 8.86÷8.59; d(1H) 8.38; m(2H) 8.06; m(5H) 7.31÷7.16; s(2H) 4.56; t(2H) 3.24; q(2H) 2.64.
13C-NMR (DMSO; 50.3 MHz)
149.87; 149.58; 137.06; 136.79; 136.41; 136.15; 136.01
(2c); 135.63; 135.02; 134.55; 133.23.; 132.84; 129.19; 129.10; 128.85 (3c); 128.59; 128.53 (2c); 128.16; 121.05; 120.86; 51.34; 46.71; 40.69.
EXAMPLE 10
N-cyclohexyl-N,N'-bis-(5-isoquinolinesulfonyl)- ethylenediamine.
Yield: 21%; melting point 226-229°C
Elemental analysis:
C H N Cl S Theoretical: 52.26 5.06 9.38 11.87 10.73 Found: 51.85 5.03 9.41 11.95 10.69
1H-NMR (DCl 1N; 200 MHz)
s(1H) 10.00; s(1H) 9.94; m(9H) 8.89÷8.50; t(1H) 8.90; t(1H) 8.04; m(1H) 3.65; m(2H) 3.19;m(2H) 2.90; m(10H) 1.67-0.90
13C-NMR (DCl 1N; 50.3 MHz)
150.44; 149.92; 137.71; 136.78; 156.56; 135.90; 135.59 135.42; 135.04; 132.82; 132.78; 129.05; 128.99; 128.75 128.70; 57.68; 43.25; 42.84; 31.28 (2C); 25.49 (2C) 24.86.
EXAMPLE 11
N-(5-isoquinolinesulfonyl)-N'-methy1-N'-(1-naphthalene- sulfonyl)-ethylenediamine
A) 7.6 g (0.034 mol) of 1-naphthalene sulfonyl chloride were added in small portions to a solution of 6 ml (0.067 mol) of N-methylenediamine in 100 ml of methylene chloride and 9.4 ml of triethylamine.
The solution was kept at room temperature for 16 hours, then the solvent was evaporated off. 8 g of a crude product were obtained, and it was subsequently purified on a silica gel column by eluting with a 10/l(v/v) chloroform/ethanol (95%) mixture. 5 g of the title compound were obtained. B) 1.9 ml (0.0135 mol) of triethylamine and 3.5 g (0.0135 mol) of 5-isoquinoline sulfonyl chloride hydrochloride, dissolved into 10 ml of chloroform, were dropped into a suspension of 3 g (0.009 mol) of the compound prepared in A. in 40 ml of chloroform. The mixture was kept at room temperature for 48 hours under stirring, then it was washed with water and desiccated over sodium sulfate. 4.5 g of a crude product were obtained and it was subsequently purified on a silica gel column by eluting with a 10/1.25(v/v) chloroform/ethyl acetate mixture. 3 g of the title compound were obtained.
Melting point > 201-203°C
Elemental analysis:
C H N Cl S Theoretical: 53.71 4.51 8.54 8.21 13.03 Found: 53.79 4.47 8.51 7.19 13.07 1H-NMR (DMSO; 200 MHz)
s(broad, 1H) 12.55; s(1H) 9.98; m(2H) 8.90÷8.81; m(2H) 8.77÷8.68; d(1H) 8.58; m(1H) 8.50; d(1H) 8.25; m(3H) 8.12÷7.97; m(3H) 7.73÷7.60; t(2H) 3.14; q(2H) 3.02; s(3H) 2.71.
13C-NMR (DMSO; 50.3 MHz)
150.06; 136.95; 136,21; 135.67 135.56 134.56
134.35; 133.61; 132.96; 129.41 129.23 129.07
128.82; 128.49; 128.19; 127.30 124.92 124.77
120.97 48.90; 40.65; 34.87.
EXAMPLE 12
N-(5-isoquinolinesulfonyl)-N-methyl-N'-(1-naphthalenesulfonyl)-ethylenediamine hydrochloride. A) 2.94 g (0.0135 mol) of diter-butoxy dicarbonate (Boc20) in 10 ml of chloroform were dropped into a solution of 2 g (0.027 mol) of N-methyl-ethylenediamine in 15 ml of chloroform. The mixture was kept at room temperature overnight (about 20 hours), then the solvent was evaporated off. 3.5 g of a crude product were obtained, and it was subsequently purified on a silica gel column by eluting with a 9/1 (v/v) chloroform/methanol mixture. 1.53 g of N'-carbobenzoxy-N'-methyl-ethylenediamine were obtained. (Yield: 65%)
B) 0.77 g (0.0034 mol) of 1-naphthalenesulfonyl chloride were added in small portions to a solution of 0.592 g (0.0034 mol) of the compound prepared in A. in 10 ml of methylene chloride and 0.47 ml (0.0034 mol) of triethylamine. The solution was kept at room temperature for 14 hours, then it was washed with water (2x25 ml) to eliminate triethylamine hydrochloride, the organic phase was essiccated over sodium sulfate and the solvent was evaporated off. The crude product was treated with 5 ml of methanol saturated with HCl at room temperature, giving 1.4 g of crude N-methyl-N'-(1-naphthalene- sulfonyl)-ethylenediamine hydrochloride. 0.9 g (0.0068 mol) of 5-isoquinoline sulfonyl chloride hydrochloride and 0.9 g (0.0068 mol) of triethylamine, dissolved into 10 ml of methylene chloride, were dropped into the dispersion of the so obtained crude compound in 20 ml of methylene chloride, at 0°C, and the mixture was kept at room temperature for 48 hours under stirring. Then the mixture was washed with water (2x5 ml) and essiccated over sodium sulfate. 2.4g of a crude product were obtained and it was subsequently purified on a silica gel column by eluting with a 10/1.25 (v/v) chloroform/ethyl acetate mixture. 1.3 g of the title compound were obtained. The compound was dissolved into 10 ml of methanol saturated with 3N HCl and after evaporation and crystallization from methanol 1.0 g of the product were obtained.
Melting point 205-207°C (methanol)
Elemental analysis:
C H N Cl S Theoretical: 53.71 4.51 8.54 7.21 13.03 Found: 53.65 4.48 8.70 7.35 12.87 1H-NMR (DMSO; 200 MHz)
s(broad, 1H) 13.94; s(1H) 9.97; m(3H) 8.79÷8.69; m(2H) 8.60÷8.47; m(2H) 8.23÷8.16; m(3H) 8.10÷7.99; m(3H) 7.72÷7.58; t(2H) 3.16; q(2H) 2.91; s(3H) 2.81.
13C-NMR (DMSO; 50.3 MHz)
149.99; 137.09; 136.78; 135.97; 135.54; 134.14 (2c); 133.69; 133.43; 129.25; 129.12; 128.88; 128.66; 128.19; 127.68; 127.19; 124.81 (2c); 120.91; 48.98; 40.55; 34.70.
EXAMPLE 13
N-(5-isoquinolinesulfonyl)-N'-(1-naphthalenesulfonyl)- ethylenediamine hydrochloride.
2 g (0.00882 mol) of 1-naphthalene sulfonyl chloride were added at room temperature to a solution of 1.2 ml (0.01764 mol) of ethylenediamine in 20 ml of methylene chloride. The solution was kept at room temperature for 12 hours, then it was washed with water (2x5 ml), the organic phase was essiccated over sodium sulfate and the solvent was evaporated off, thus giving 2.8 g of a crude product which was dissolved into 30 ml of methylene chloride and treated at room temperature with 2.44 ml (0.01 )of triethylamine and 2.2 g (0.0088 mol) of 5 q inoline sulfonyl chloride hydrochloride.The resulting mixture was kept at room temperature for 14 hours under stirring. Then the mixture was washed with water (2x10 ml), the organic phase was separated, essiccated over sodium sulfate and evaporated to dryness. 4.2 g of a crude product were obtained and it was subsequently purified on a silica gel column by eluting with a 10/0.3 (v/v) chloroform/ethanol(95%) mixture. 2.8 g of the title compound were obtained. The compound was dissolved into methanol saturated with 3N HCl, which 2.15 g of the title compound crystallized from. (Yield 51%).
Melting point 224-226°C (methanol)
Elemental analysis:
C H N Cl S Theoretical: 52.77 4.22 8.79 7.42 13.41 Found: 52.80 4.34 8.72 7.64 13.44 1H-NMR (DMSO; 200 MHz)
s(1H) 9.98; s(broad, 1H) 9.86; m(2H) 8.84÷8.76; d(1H) 8.71; t(1H) 8.63; m(2H) 8.55÷8.49; d(1H) 8.19; m(4H) 8.12÷7.94; m(3H) 7.69+7.55; m(4H) 2.74.
13C-NMR (DMSO; 50.3 MHz)
149.72; 136.46; 136.27; 135.63; 135.51; 135.34; 134.13 (2c); 132.98; 129.25 (2c); 129.16; 128.72; 128.18; 127.59; 127.17; 124.77 (2c); 121.13; 42.08. EXAMPLE 14
1-(5-isoquinolinesulfonyl)-2-methyl-4-(1-naphthalene- sulfonyl)-piperazine .
According to the procedure of the example 11 and using 2-methylpiperazine instead of N-methyl-ethylene- diamine the title compound was obtained with a yield of
28%.
Melting point 235-240°C
Elemental analysis:
C H N Cl S
Theoretical: 55.64 4.67 8.11 6.84 12.38 Found: 55.78 4.72 8.06 6.81 12.43
1H-NMR (DMSO; 200 MHz)
s(1H) 9.95; m(3H) 8.81÷8.61; d(1H) 8.46; m(1H) 8.33; t(2H) 8.6; m(2H) 8.07÷7.97; m(3H) 7.66÷7.54; m(1H)
4.18; m(2H) 3.67; d(1H) 3.47; m(1H) 3.29; m(2H)
2.31÷2.06; d (3H) 1.02.
13C-NMR (DMSO; 50.3 MHz)
150.60; 138.04; 137.56; 136.44; 134.84; 134.17; 134.02; 133.05; 131.24; 130.38; 129.41; 128.76; 128.64; 128.47;
127.66; 127.22; 124.83; 124.20; 120.21; 49.88; 47.89
(2c); 45.09; 15.10.
EXAMPLE 15
1-(5-isoquinolinesulfonyl)-2-methyl-4-(N-methyl- 1,2,3,4-tetrahydro-5-isoquinolinesulfonyl)-piperazine .
According to the procedure of the example 7 A. and using 6.7 g (0.067 mol) of 2-methylpiperazine instead of N-methylethylenediamine, and 8.35 g (0.034 mol) of
1-methyl-1,2,3,4-tetrahydro-5-isoquinol inesulf onyl chloride, 2-methyl-4-(N-methyl-1,2,3,4-tetrahydro-5- isoquinolinesulfonyl)-piperazine was obtained. According to the procedure of the example 11 B and using 1 g (0.003 mol) of 2-methyl-4-(N-methyl-1,2,3,4- tetrahydro-5-isoquinolinesulfonyl)-piperazine, 1.6 g (0.006 mol)of 5-isoquinolinesulfonyl chloride, hydrochloride and 0.8 ml (0.006 mol) of triethylamine, 2.8 g of a crude product were obtained; the crude was subsequently purified on a silica gel column eluted with a 9/0.5/0.01 (v/v) chloroform/methanol/ammonia mixture obtaining 1.3 g of the title product in the form of hydrochloride.
Melting point 190-195°C
Elemental analysis:
C H N Cl S Theoretical: 47.29 5.62 9.19 11.63 10.52 Found: 47.11 5.58 9.08 11.58 10.49
1H-NMR (DMSO; 200 MHz)
s(broad, 1H) 11.84; s(1H) 9.93; d(1H) 8.80; d(1H) 8.74; d(1H) 8.65; d(1H) 8.53; t(1H) 8.06; d(1H) 7.67; d(1H) 7.56; t(1H) 7.46; m(5H) 4.66÷4.13; m(8H) 3.71÷3.22; s(3H) 3.71; m(2H) 2.70÷2.24; t(3H) 1.11.
13C-NMR (DMSO; 50.3 MHz)
150.58; 138.42 (2c); 137.21; 136.08; 134.05; 132.41 132.26; 132.02; 131.43; 129.52; 129.23; 128.80 (2c) 127.21; 120.03; 53.33; 49.50; 48.27 (2c); 45.13; 42.02 23.81; 15.30.
EXAMPLE 16
N-(5-isoquinolinesulfonyl)-N'-(N-methyl-1,2,3,4- tetrahydro-5-isoquinolinesulfonyl)-ethylenediamine.
According to the procedure of the example 11 and using 1-methyl-1,2,3,4-tetrahydro-5-isoquinolinesulfonyl chloride instead of 1-naphthalenesulfonyl chlo ride, the title compound was obtained in the form of hydrochloride with a yield of 12%.
Melting point 245-250°C
Elemental analysis:
C H N Cl S
Theoretical: 47.28 4.91 10.50 13.29 12.02 Found: 47.16 4.94 10.47 13.23 12.20
1H-NMR (DMSO; 200 MHz)
s(broad, 1H) 11.48; s(1H) 9.94; m(2H) 8.81; d(1H) 8.72; t(1H) 8.66; d(1H) 8.55; t(1H) 8.10; t(1H) 8.07; dd(1H)
7.65; m(2H) 7.49÷7.37; m(12H) 4.59÷2.74.
13C-NMR (DMSO; 50.3 MHz)
150.19; i:3.28; 138.23; 135.95; 135.45; 135.33; 132.67; 131.49; 131.40; 130.15; 128.87; 128.71; 128.09; 127.06; 120.78 53.32; 49.40; 42.37; 42.29; 42.08; 23.24.
The following compounds were obtained substantially using the same reactants described in the above examples.
- 1,2-Dimethyl-N,N'-bis-(5-isoquinolinesulfonyl)- ethylenediamine.
- N,N'-bis-(5-isoquinolinesulfonyl)-1-methyl-ethylenediamine.
- N,N'-bis-(5-isoquinolinesulfonyl)-1-propyl-ethylenediamine.
- N,N'-bis-(5-isoquinolinesulfonyl)-cyclohexylene1,3-diamine. - N-phenyl-N,N'-bis-(5-isoquinolinesulfonyl)-ethylenediamine. - N,N'-bis-(5-isoquinolinesulfonyl)-N-propyl-ethylenediamine.
- N,N'-bis-(5-isoquinolinesulfonyl)-N-methyl-1- methyl-ethylenediamine.
- N,N'-bis-(5-isoquinolinesulfonyl)-N-methyl-2- methyl-ethylenediamine.
- N,N'-bis-(5-isoquinolinesulfonyl)-N-methyl-2- propyl-ethylenediamine.
- N,N'-bis-(5-isoquinolinesulfonyl)-N-methyl-cyclohexylene-1,2-diamine.
- 1-(4-chlorobenzyl)-N,N'-bis-(5-isoquinolinesulfonyl)-ethylenediamine.
- N,N'-bis-(5-isoquinolinesulfonyl)-1-(4-nitroben- zyl)-ethylenediamine.
- N-(4-chlorobenzyl)-N,N'-bis-(5-isoquinolinesulfonyl)-ethylenediamine.
- N,N'-bis-(5-isoquinolinesulfonyl)-N-(4-nitroben- zyl)-ethylenediamine.
The compounds of the present invention are active as inhibiting agents of the protein kinases, therefore are partially useful in cardiovascular pathologies, as well as in the inflammatory and immune diseases, in oncology and in organ transplants.
The inhibiting activity of the present compounds is illustrated by the following test:
IN VITRO PROTEIN KINASE INHIBITING ACTIVITY
Some compounds of the invention have been tested as to the protein kinase A and C inhibiting activity by using partially purified preparates of these enzymes, obtained according to the method of U. Kikkawa et al., Biochem. Bioph. Res. Commun., vol 135, No. 2 (1986). The inhibiting activity of the tested compounds, which have been administered at 100 μM concentration, is expressed as percent of the protein kinase A and C acti vity, the latter being measured by the evaluation of the 32P coming from bovine histon 32P-ATP according to the method described by U. Kikkawa et al., J. Biol. Chem., vol. 257, p. 13341-13345 (1982). The results are shown in Table 1.
Figure imgf000023_0001
A further object of the present invention is the use of the new compounds as protein kinase inhibiting agents, with reference to the acts and aspects industrially appilcable of said use, the incorporation thereof in pharmaceutical compositions.
For the foreseen therapeutic uses, the compounds of formula I can be administered appropriately formulated in pharmaceutical compositions, according to what descibed for example in "Remington's Pharmaceutical Sciences Handbook", Mack Pub. Co. XVII ed. N.Y., USA. Examples of pharmaceutical compositions are sugar coated pills, capsules, syrups, suppositories, parente rally administrable ampoules, microgranules and the like. The posology will obviously depend on more factors, such as type and gravity of the pathologies to be treated and patient conditions (weight, sex, age, etc.).

Claims

1. Compounds of general formula I
SO2RSO2X
I
Figure imgf000025_0001
wherein R is the group -N-R3-N-, where R1 and R2 are
Figure imgf000025_0002
Figure imgf000025_0003
R1 R2
independently hydrogen, methyl, ethyl, straight or branched C3-C6 alkyl, benzyl, optionally substituted by at least one substituent selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, nitro, amino, C1-C6 alkylamino di-C1-C6 alkylamino, aliphatic C2-C6 acylamino, C1-C6 carboxyamido, carbonyl, carboxyl, esterified carboxyl, cyano, methylenedioxy, and R3 is straight or branched (C2- Cg)alkylene, optionally substituted by benzyl or benzyl substituted by at least one substituent selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, C1-C6 aikoxy, nitro, amino, C1-C6 alkylamino di-C1-C6 alkylamino, aliphatic C2-C6 acylamino, C1-C6 carboxyamido, carbonyl, carboxyl, esterified carboxyl, cyano, methylenedioxy or C5-C8 cycloalkylene; or R is the bivalent residue of a 4-8 membered heterocyclic group, bound to SO2 groups through nitrogen atoms, optionally substituted by at least one C1-C4 alkyl group; X is an aromatic, partially or totally hydrogenated isoquinoline group, optionally substituted by at least one C1-C4 alkyl group, or the partially or totally hydrogenated naphthyl group and optionally substituted with at least one C1-C4 alkyl group; the salts with pharmaceutically acceptable acids thereof.
2. The use of the compounds according to claim 1 as therapeutic agents useful in cardiovascular pathologies, in the inflammatory and immune diseases, in oncology and in organ transplants.
3. The use of the compounds according to claim 1 as protein kinase A inhibiting agents.
4. Pharmaceutical compositions useful in therapy for the treatment of cardiovascular pathologies, in the inflammatory and immune diseases, in oncology and in organ transplants, containing a therapeutically effective amount of at least one compound according to claim 1 together with at least one pharmaceutically acceptable carrier or excipient.
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