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1. (WO2006085228) 9A-CARBAMOYL-Y-AMINOPROPYL AND 9A-THIOCARBAMOYL-Y-AMINOPROPYL-AZALIDES WITH ANTIMALARIAL ACTIVITY
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CLAIMS

1. A compound of formula (I),



C)
wherein
R represents H or cladinosyl group of formula (II);


R represents H, β-cyanoethyl, β-amidoethyl or β-(C1-4alkoxycarbonyl)ethyl;

R2 represents
a) C1-12 alkyl, wherein C1-12 alkyl is
i) uninterrupted or interrupted by 1-3 bivalent radical groups selected from -O, -S- and -N(R3)- ; and/or

ii) linear or branched, and unsubstiruted or substituted by 1-3 groups selected from halogen (OH; NH2; N-(C1-C4)alkylamino; N,N-di(CrC4- alkyl)amino, CN, NO2; C(O)OCMalkylaryl, (C1-C4-alkyl)-thio; a C3-14 membered saturated, unsaturated or aromatic carbocycle optionally substituted with one or more substituents selected from halogen, CN, C1-4alkyl unsubstituted or substituted with 1 to 3 halogen, O(C1-4alkyl) optionally substituted with 1 to 3 halogen, S(C1-C4-alkyl), 0(C3-6 cycloalkyl), O(C1-4alkylaryl), C1-4alkylcyano, C(O)C 1-4alkyl, C1-4 alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)C1-4alkylaryl, C(O)OC1-4alkylaryl, NO2, diazoaryl, sulfo- 5 or 6 membered carbocyclic or heterocyclic ring, C1-4alkyl- C(O)-O-C1-4alkyl and C1-4alkylO-C(O)-NR3; a C3-14 membered saturated, unsaturated or aromatic heterocycle containing 1 to 3 heteroatoms selected from the group nitrogen, oxygen, sulphur optionally substituted with halogen, CN, C1-4alkyl unsubstituted or substituted with 1 to 3 halogen, O(C1-4alkyl) optionally substituted with 1 to 3 halogen, S(C1-C4-alkyl), 0(C3-6 cycloalkyl), 0(C1- 4alkylaryl), C1-4alkylcyano, C(O)C1-4alkyl, C(O)OC1-4alkylaryl; C1-4 alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)C1-4alkylaryl, NO2, diazoaryl, sulfo- 5 or 6 membered carbocyclic or heterocyclic ring, C1-4alkyl-C(O)-O-C1-4alkyl and C1- 4alkylO-C(O)-NR3; or

b) C2-6 alkenyl containing O, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituents selected from halogen; CN; NO2,;

OH; NH2; N-(C1-C4)alkylamino; N,N-di(C1-C4-alkyl)amino; optionally substituted aryl; optionally substituted heteroaryl; or

c) C3-14 membered saturated, unsaturated or aromatic carbocycle which is unsubstituted or substituted by 1-3 groups selected from halogen; OH; CN; C1-4alkyl unsubstituted or substituted with 1 to 3 halogen (preferably trifluoromethyl) or CN group; O(C1-4alkyl) optionally substituted with 1 to 3 halogen; S(C1-C4-alkyl); 0(C3-6 cycloalkyl); O(C1-4alkylaryl); C(O)C1-4alkyl; C(O)OC1-4alkylaryl; C1-4 alkyloxycarbonyl; optionally substituted aryl; optionally substituted heteroaryl; C(O)C1-4alkylaryl; NO2; N-(C1-C4)alkylamino; N,N-di(C1-C4-alkyl)amino diazoaryl; sulfo- 5 or 6 membered carbocyclic or heterocyclic ring; C1-4alkyl-C(O)-O-C1-4alkyl and C1-4alkylO-C(O)-NR3; or d) C3-14 membered saturated, unsaturated or aromatic heterocycle containing 1 to 3 heteroatoms selected from the group nitrogen, oxygen, sulphur optionally substituted by 1-3 groups selected from halogen; CN; C1-4alkyl unsubstituted or substituted with 1 to 3 halogen; O(C1-4alkyl) optionally substituted with 1 to 3 halogen; S(C1-C4-alkyl); 0(C3-6 cycloalkyl); O(C1-4alkylaryl); C^alkylcyano; C(O)C1-4alkyl; C1-4 alkyloxycarbonyl; optionally substituted aryl; optionally substituted heteroaryl; C(O)C1-4alkylaryl; C(O)OC1-4alkylaryl; NO2; diazoaryl; 5 or 6 membered carbocyclic or heterocyclic ring; sulfo- 5 or 6 membered carbocyclic or heterocyclic ring; C1-4alkyl-C(O)-O-C1-4alkyl and C1-4alkylO-C(O)-NR3;

e) C(O)aryl;

R3 represents H or C1-4 alkyl;

X represents O or S;

n is 2 or 3;

provided that when R1 is H or β-cyanoethyl and n is 3, R2 cannot be isopropyl, 1-naphtyl, 2-naphtyl, benzyl, 2-(trifluoromethyl)phenyl, 3-phenylpropyl, β-phenylethyl, ethoxycarbonylmethyl, l-(l-naphtyl)ethyl, 3,4,5-trimethoxyphenyl or 2,4-dichlorophenyl group.

or a pharmaceutically acceptable derivative thereof.

2. The compound of claim 1, wherein
R represents H or cladinosyl group of formula (II)

R1 represents H, β-cyanoethyl, β-amidoethyl or β-(C1-4alkoxycarbonyl)ethyl;

R2 represents
a) C1-12 alkyl, wherein C1-12 alkyl is
i) linear or branched, and unsubstituted or substituted by 1-3 groups selected from halogen, N,N-di(C1-C4-alkyl)amino, C(O)OC1-4alkylaryl, (C1- C4-alkyl)thio or; phenyl, naphthyl, aryl, furyl, cycloalkyl, thiophenyl, 3,4- methylenedioxyphenyl, morpholinyl, or piperidinyl optionally substituted with one or more substituents selected from halogen, C1-4alkyl unsubstituted or substituted with 1 to 3 halogen, O(C1-4alkyl), 0(C3-6 cycloalkyl), 0(C1- 4alkylaryl), C(O)C1-4alkyl, C1-4 alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)C1-4alkylaryl, C(O)OC1-4alkylaryl;

b) an unsubstituted C2-6 alkenyl; or

c) C1-12 cycloalkyl, adamantyl, norbornyl, norbornenyl, phenyl, indanyl, or naphthyl; any of which is unsubstituted or substituted by 1-3 groups selected from halogen; CN; C1-4alkyl unsubstirαted or substituted with 1 to 3 of halogen or CN group; O(C1-4alkyl) optionally substituted with 1 to 3 halogen; S(C1-C4-alkyl); 0(C3-6 cycloalkyl); O(C1-4alkylaryl); C(O)C1-4alkyl; C1-4 alkyloxycarbonyl; aryl; heteroaryl; NO2; N,N-di(C1-C4-alkyl)amino, diazoaryl; and piperidinylsulfonamido; or

d) dihydrobenzofuranyl, C1-3 alkylenedioxyphenyl, benzopyranyl, furyl, isoxazolyl, piperidinyl, pyridinyl, thiophenyl, benzothiadiazolyl, tetrahydrobenzothiphenyl, optionally substituted by 1-3 groups selected from halogen; C1-4alkyl unsubstituted or substituted with 1 to 3 halogen; C1-4 alkyloxycarbonyl; optionally substituted aryl; optionally substituted heteroaryl; C(O)OC1-4alkylaryl; or phenoxy;

e) C(O)aryl;

X represents O or S; and n is 2 or 3.

3. The compound of claim 2, wherein,
R represents H or cladinosyl group of formula (II)



R1 represents H, β-cyanoethyl, β-amidoethyl or β-(C1-4alkoxycarbonyl)ethyl;

R2 represents
a) 3-phenylpropyl, β-phenylethyl, ethoxycarbonylmethyl, isopropyl, 1-(1- naphthyl)-ethyl, t-butyl, n-butyl, sec-butyl, benzyl, 2-furylmethyl, A- methoxybenzyl, cyclohexylmethyl, ethyl, 2-(2-methyl-5,5-dimethyl)-pentyl, 2- (2-thophenyl)-ethyl, 3 -thiomethylpropyl, 3 ,4-methylenedioxyphenylmethyl, N-morpholinylethyl, N-morpholinylpropyl, trityl, N-piperidinylethyl, 3- diethylaminopropyl, diphennylmethyl, 3-chloropropyl, isobutyl; or

b) 2-propenyl; or

c) cyclopentyl, cyclopropyl, cyclododecyl, norbornyl, norbornenyl, 2-benzyloxycyclohexyl, adamantyl, phenyl, 1-naphthyl, 4-chlorophenyl, 2-trifluoromethylphenyl, 3,4,5-trimethoxyphenyl, 2-naphthyl, 2,4-dichlorophenyl, A-cyanophenyl, cyclohexyl, 4-ethylphenyl, 4-methoxyphenyl, 2-methyl-5 -fluorophenyl, 4-cyanomethylphenyl, indanyl, 4-acetylphenyl, 2-phenylphenyl, 3-thiomethylphenyl, 3,5-dimethoxycarbonylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,4-difluorophenyl, 3-chlorophenyl, 3 -fluorophenyl, 3-cyclopentoxy-4-Methoxyphenyl, A-benzyloxyphenyl, 2-ethylphenyl, 2,6-difluorophenyl, 4-nitrophenyl, 3,5-dichlorophenyl, 2-methoxy-4-nitrophenyl, ethoxycarbonylphenyl, 2-trifluoromethylphenyl, 4-phenylazophenyl, 4-diethylaminophenyl, 3-nitrophenyl, 3-chloro-4-trifluoromethylphenyl, 3,4-dichlorophenyl, 2,3,4-trifluorophenyl, A-bromophenyl, 4-diazolylphenyl, 4-piperadylsulfonamidophenyl, l-(4- dimethylamino)-naphthyl, 4-isopropylphenyl, 4-difluoromethoxyphenyl, or 2-methoxy-5-phenylphenyl; or

d) 3,4-methylenedioxyphenyl, 6-fluorobenzo-l,3-pyranyl, dihydrobenzofuranyl, 3,4-propylenedioxyphenyl, 3-(2-trifluoromethyl-5-methyl)-furyl, 4-(3,5-dimethyl)-isoxazole, 4-(3-phenyl-5-methyl)-isoxazole, benzyloxycarbonylpiperidinyl, 4-(2,6-dichloro)-pyridinyl, 2-thiophenyl, benzothiadiazolyl, 3-(2-methoxycarbonyl)-thiophenyl, 2-(3-methoxycarbonyl)-tetrahydrobenzothiophenyl, pyridinyl, 5-(2-morpholinyl)-pyridinyl, 5-(2-phenoxy)-pyridinyl; or

e) C(O)aryl;

X represents O or S; and

n is 2 or 3.

4. Process for the preparation of the compound of formula (I),



(I)
wherein
R represents H or cladinosyl group of formula (II);

R1 represents H, β-cyanoethyl, β-amidoethyl or β-(C1-4alkoxycarbonyl)ethyl;

R2 represents
a) C1-12 alkyl, wherein C1-12 alkyl is
iii) uninterrupted or interrupted by 1-3 bivalent radical groups selected from -O-, -S- and -N(R3)- ; and/or

iv) unsubstituted or substituted by 1-3 groups selected from halogen; OH;
NH2; N-(Ci-C4)alkylamino; N,N-di(C1-C4-alkyl)amino; CN, NO2;
C(O)OC1-4alkylaryl; a C3-14 membered saturated, unsaturated or aromatic carbocycle optionally substituted with one or more substituents selected from halogen, CN, C1-4alkyl unsubstituted or substituted with 1 to 3 halogen, O(C1-4alkyl) optionally substituted , with 1 to 3 halogen, S(CrC4-alkyl), 0(C3-6 cycloalkyl), 0(C1- 4alkylaryl), C1-4alkylcyano, C(O)C1-4alkyl,

C1-4 alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)C1-4alkylaryl, C(O)OC1-4alkylaryl, NO2, diazoaryl, sulfo- 5 or 6 membered carbocyclic or heterocyclic ring, C1- 4alkyl-C(O)-O-C1-4alkyl and C1-4alkylO-C(O)-NR3; a C3-14 membered saturated, unsaturated or aromatic heterocycle containing 1 to 3 heteroatoms selected from the group nitrogen, oxygen, sulphur optionally substituted with halogen, CN, C1-4alkyl unsubstituted or substituted with 1 to 3 halogen, O(C1-4alkyl) optionally substituted with 1 to 3 halogen, S(CrC4-alkyl), 0(C3-6 cycloalkyl), 0(C1- 4alkylaryl), C1-4alkylcyano, C(O)C1-4alkyl, C(O)OC1-4alkylaryl; C1-4 alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)C1_4alkylaryl, NO2, diazoaryl, sulfo- 5 or 6 membered carbocyclic or heterocyclic ring, C1-4alkyl-C(O)-O-C1-4alkyl and C1- 4alkyl0-C(0)-NR3; or

b) C2-6 alkenyl containing O, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituents selected from halogen; CN; NO2;;

OH; NH2; N-(C1-C4)alkylamino; NjN-d^CrQ-alkytyamino; optionally substituted aryl; optionally substituted heteroaryl; or

c) C3-14 membered saturated, unsaturated or aromatic carbocycle which is unsubstituted or substituted by 1-3 groups selected from halogen; OH; CN; C1-4alkyl unsubstituted or substituted with 1 to 3 halogen or CN group; O(C1-4alkyl) optionally substituted with 1 to 3 halogen; S(CrC4-alkyl); 0(C3-6 cycloalkyl); O(C1-4alkylaryl); C(O)C1-4alkyl; C(O)OC1-4alkylaryl; C1-4 alkyloxycarbonyl; optionally substituted aryl; optionally substituted heteroaryl; C(O)C1-4alkylaryl; NO2; diazoaryl; sulfo- 5 or 6 membered carbocyclic or heterocyclic ring; C1-4alkyl-C(O)-O-C1-4alkyl and C1- 4alkylO-C(O)-NR3; or

d) C3-14 membered saturated, unsaturated or aromatic heterocycle containing 1 to 3 heteroatoms selected from the group nitrogen, oxygen, sulphur optionally substituted by 1-3 groups selected from halogen; CN; C1-4alkyl unsubstituted) or substituted with 1 to 3 halogen; O(C1-4alkyl) optionally substituted with 1 to 3 halogen; S(C1-C4-alkyl); 0(C3-6 cycloalkyl); O(C1-4alkylaryl); C1-4alkylcyano; C(O)C1-4alkyl; C1-4 alkyloxycarbonyl; optionally substituted aryl; optionally substituted heteroaryl; C(O)C1-4alkylaryl; C(O)OC1-4alkylaryl; NO2; diazoaryl; 5 or 6 membered carbocyclic or heterocyclic ring; sulfo- 5 or 6 membered carbocyclic or heterocyclic ring; C1-4alkyl-C(O)-O-C1-4alkyl and C1-4alkylO-C(O)-NR3;

e) C(O)aryl;

R3 represents H or C1-4 alkyl;

X represents O or S;

n is 2 or 3;

provided that when R1 is H or β-cyanoethyl and n is 3, R2 cannot be isopropyl, 1-naphtyl, 2-naphtyl, benzyl, 2-(trifluoromethyl)phenyl, 3-phenylpropyl, β-phenylethyl, ethoxycarbonylmethyl, l-(l-naphtyl)ethyl, 3,4,5-trimethoxyphenyl or 2,4-dichlorophenyl group;

or a pharmaceutically acceptable derivative thereof, wherein

a compound of formula (III)



(HI)

is reacted with an isocyanate or a thioisocyanate of formula (IV),

R2 — N= C=X
(IV)

in an aprotic solvent selected from toluene, xylene and dichloromethane, at a temperature from about 0° to HO0C.

5. A method for the therapeutic and/or prophylactic treatment of malaria in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of compound according to claim 1.

6. The method of claim 5, wherein the subject has been infected with Plasmodium falciparum.

7. The method of claim 5, wherein the subject has been infected with P. vivax.

8. The method of claim 5, wherein the subject has been infected with P. ovale.

9. The method of claim 5, wherein the subject has been infected with P. malariae.

10. The method of claim 5, wherein the compound is administered after the subject has been exposed to the malaria parasite.

11. The method of claim 5, wherein the compound is administered before the subject travels to a country where malaria is endemic.

12. The method of claim 11, wherein the malaria parasite is a drug-resistant malarial strain.

13. The method of claim 12, wherein the drug-resistant malarial strain is resistant to at least one of chloroquine, mefloquine, halofantrine, artemisinin, atovaquone/proguanil, doxycycline or primaquine.

14. The method of claim 5, wherein the subject is a mammal.

15. A pharmaceutical preparation comprising the compound of claim 1 and at least one pharmaceutically acceptable carrier.

16. The pharmaceutical preparation of claim 13, wherein the preparation is for the treatment of malarial infections.