RU2003112211A - LIGANDS OF MELANOCORTINE RECEPTORS - Google Patents

Claims (19)

1. The compound having a structure corresponding to formula (I):

where (A) X is selected from hydrogen, fluorine, aryloxy, acyloxy, OR ¹ , SR ¹ , -NR ¹ R ^{1 '} and –CHR ¹ R ^1' , where R ¹ and R ^{1 'are} independently selected from the group consisting of hydrogen alkyl and acyl; (B) (1) each R ^{2 is} independently selected from the group consisting of hydrogen, alkyl, halogen, and heteroalkyl; or (2) (a) two adjacent R ² substituents, or adjacent R ² and R ³ substituents, may be combined to form a (3-8) membered carbocyclic or heterocyclic ring; or (b) R ² bonded to a carbon atom that is bonded to X and Z ¹ and the substituent R ⁵ may optionally combine to form a carbocyclic or heterocyclic ring that is fused to the phenyl ring J; or; (c) R ² bonded to a carbon atom that is bonded to an Ar ring can combine with R ⁷ to form a ring fused to an Ar ring; or (d) R ² bonded to a carbon atom that is bonded to Z ² and Z ³ may optionally bind to R ⁸ to form a carbocyclic or heterocyclic ring; or (e) R ² bonded to a carbon atom that is bonded to Z ³ and D may optionally bind to R ¹⁰ to form a carbocyclic or heterocyclic ring; (C) each of Z ¹ , Z ² and Z ^{3 is} independently selected from —OC (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) O-; -S (O) _a C (R ³ ) (R ^3a ) -, where a is 0, 1 or 2; —C (R ³ ) (R ^3a ) S (O) _b -, where b is 0, 1 or 2; -N (R ^3e ) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) N (R ^3e ) -; -C (O) N (R ^3d ) -; -N (R ^3d ) C (O) -; -C (O) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) C (O) -; -C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -; -C (R ³ ) = C (R ^3a ) -; -C≡C-; -SO ₂ N (R ^3d ) -; -N (R ^3d ) SO ₂ -; -C (R ³ ) (R ^3a ) P (= O) (OR ^3f ) -; -P (= O) (OR ^3f ) C (R ³ ) (R ^3a ) -; -N (R ^3d ) P (= O) (OR ^3f ) -; -P (= O) (OR ^3f ) N (R ^3d ) -; -P (= O) (OR ^3f ) O-; -OP (= O) (OR ^3f ) -; cycloalkyl having from 3 to 8 ring atoms and heterocycloalkyl having from 4 to 8 ring atoms; Where (1) each of R ³ , R ^3a , R ^3b and R ^3c , when present, is independently selected from hydrogen, hydroxy, alkoxy, aryloxy, acyloxy, thiol, alkylthio, acylthio, arylthio, amino, alkylamino, acylamino and alkyl; (2) R ^3d , when present, is selected from hydrogen, alkyl and aryl; (3) R ^3e , when present, is selected from hydrogen, alkyl, aryl and acyl; and (4) R ^3f , when present, is selected from hydrogen and alkyl; (D) p is 0, 1, 2, 3, 4 or 5; Where (1) when p is greater than 0, each R ⁴ and R ^{4 ′ is} independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, and acylamino; (2) when p is greater than 1, two R ⁴ substituents, together with the carbon atoms to which they are bonded, can join to form a heterocycloalkyl, cycloalkyl or aryl ring; and (3) when p is greater than 1, the substituents R ⁴ at two adjacent carbon atoms can both be zero, so that a double bond is formed between two adjacent carbon atoms, or both substituents R ⁴ and both substituents R ^{4 '} at two adjacent atoms carbon can all be zero, so that a triple bond is formed between two adjacent carbon atoms; (E) R ⁵ represents 5 substituents (i.e., positions 2-6) in the phenyl ring J, where each R ^{5 is} independently selected from hydrogen, hydroxy, halogen, thiol, —OR ¹² , —SR ¹² , —SO ₂ N (R ^1Z ) (R ^{12 ′} ), —N (R ¹² ) (R ^{12 ′} ), alkyl, acyl, alkene, alkyno, cyano, nitro, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; where each R ¹² and R ^{12 ′ is} independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; or two R ⁵ substituents may optionally combine to form a carbocyclic or heterocyclic ring that is fused to the phenyl ring J; (F) q is 0, 1, 2, 3, 4, or 5; Where (1) when q is greater than 0, each R ⁶ and R ^{6 ′ is} independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, and acylamino; (2) when q is greater than 1, two R ⁶ substituents, together with the carbon atoms to which they are bonded, can combine to form a heterocycloalkyl, cycloalkyl or aryl ring; and (3) when q is greater than 1, the substituents R ⁶ at two adjacent carbon atoms can be zero, so that a double bond is formed between two adjacent carbon atoms, or both substituents R ⁶ and both substituents R ^{6 '} at two adjacent carbon atoms can all be zero, so that a triple bond is formed between two adjacent carbon atoms; (G) Ar represents an aryl or heteroaryl ring selected from the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; (H) R ⁷ represents substituents on the Ar ring, where each R ^{7 is} selected from hydrogen, halogen, —NR ¹³ R ^{13 ′} , alkyl, acyl, alkene, alkyno, cyano, nitro, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; where each R ¹³ and R ^{13 ′ is} independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; or two R ⁷ substituents may optionally combine to form a carbocyclic or heterocyclic ring fused to the Ar ring; (I) r is 0, 1, 2, 3, 4, 5, 6, or 7; Where (1) each R ⁸ and R ^{8 ′ is} independently selected from hydrogen, alkyl, halogen, hydroxy, alkoxy, and amino; (2) when r is greater than 1, two R ⁸ substituents, together with the carbon atoms to which they are bonded, can combine to form a heterocycloalkyl, cycloalkyl or aryl ring; and (3) when r is greater than 1, the substituents R ⁸ at two adjacent carbon atoms can be zero, so that a double bond is formed between two adjacent carbon atoms, or both substituents R ⁸ and both substituents R ^{8 '} at two adjacent carbon atoms can all be zero, so that a triple bond is formed between two adjacent carbon atoms; (J) B is selected from —N (R ¹⁴ ) C (= NR ¹⁵ , = O or = S) NR ¹⁶ R ¹⁷ , —NR ²⁰ R ²¹ , cyano (—CN), a heteroaryl ring, for example, thiophene, alkyl- or a dialkylamine, a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring containing at least one nitrogen atom in the ring, where R ¹⁴ , R ¹⁵ R ¹⁶ , R ¹⁷ , R ²⁰ and R ^{21 are} independently selected from hydrogen, alkyl, alkene, and alkyn; where, in addition, a combination of two or more R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ may optionally combine with the atoms to which they are attached to form a monocyclic or bicyclic ring; preferred are —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , cyano, —N (R ¹⁴ ) C (= O) NR ¹⁶ R ¹⁷ , a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring containing at least one nitrogen atom in the ring, —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , —N (R ¹⁴ ) C (= O) NR are more preferred ¹⁶ R ¹⁷ , cyano, triazole and imidazole. (K) s is 0, 1, 2, 3, 4 or 5; Where (1) when s is greater than 0, each R ⁹ and R ^{9 ′ is} independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, and acylamino; (2) when s is greater than 1, two R ⁹ substituents, together with the carbon atoms to which they are bonded, can join to form a heterocycloalkyl, cycloalkyl or aryl ring; and (3) when s is greater than 1, the substituents R ⁹ at two adjacent carbon atoms can be zero, so that a double bond is formed between two adjacent carbon atoms, or both both substituents R ⁹ and both substituents R ^{9 '} at two adjacent carbon atoms can all be zero, so that a triple bond is formed between two adjacent carbon atoms; (L) R ^{10 is} selected from the group consisting of an optionally substituted bicyclic aryl ring and an optionally substituted bicyclic heteroaryl ring; and (M) D is independently selected from hydrogen, fluoro, hydroxy, thiol, acylthio, alkoxy, aryloxy, alkylthio, acyloxy, cyano, amino, acylamino, —C (O) R ¹¹ and —C (S) R ¹¹ ; where R ¹¹ selected from the group consisting of hydroxy; alkoxy; amino; alkylamino; -NHOR ¹⁸ , where R ^{18 is} selected from hydrogen and alkyl; —N (R ¹⁹ ) CH ₂ C (O) NH ₂ wherein R ¹⁹ is alkyl; -NHCH ₂ CH ₂ OH; -N (CH ₃ ) CH ₂ CH ₂ OH; and —NHNHC (= Y) NH ₂ , where Y is selected from O, S, and NH; and (N) where, if at least one of Z ¹ , Z ² or Z ³ is other than -C (O) N (R ^3d ) - or -N (R ^3d ) C (O) -, then X and D may optionally be joined together via a linking group (linker) L, which contains all covalent bonds or covalent bonds and an ionic bond, so as to form a cyclic peptide analogue; or its optical isomer, diastereomer or enantiomer; its pharmaceutically acceptable salt, hydrate or its biohydrolyzable ester, amide or imide. 2. The compound according to claim 1, where X is selected from –NR ¹ R ^{1 ′} and –CHR ¹ R ^{1 ′} and where R ¹ represents hydrogen or alkyl and R ^{1 ′} represents acyl. 3. The compound according to claim 1 or 2, where each R ² represents hydrogen; or R ² bonded to a carbon atom bound to Z ³ and D combines with R ¹⁰ to form a carbocyclic or heterocyclic ring, and the other R ² substituents are hydrogen. 4. The compound according to any one of the preceding paragraphs, where Z ¹ , Z ² and Z ^{3 are} independently selected from —OC (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) O-; -C (R ³ ) (R ^3a ) N (R ^3e ) -; -C (O) N (R ^3d ) -; -C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -; -C (R ³ ) = C (R ^3a ) -; -SO ₂ N (R ^3d ) - and -P (= O) (OR ^3f ) C (R ³ ) (R ^3a ) -. 5. The compound according to claim 4, where each R ³ , R ^3a , R ^3b and R ^3c , if present, is independently selected from hydrogen, hydroxy, alkoxy, aryloxy and alkyl; R ^3d , if present, is selected from hydrogen and alkyl; R ^3e , if present, is selected from hydrogen and alkyl; and if R ^{3f is} present and is alkyl, then said R ^3f is branched alkyl. 6. The compound according to claim 1, where p is 1 or 2. 7. The compound according to claim 1, where each R ⁴ , if present, is hydrogen, and each R ^{4 '} , if present, is hydrogen or alkyl. 8. The compound according to claim 1, where each R ⁵ independently selected from hydrogen; hydroxy; halogen; thiol; —SO ₂ N (R ¹² ) (R ^{12 ′} ), wherein R ¹² and R ^{12 ′ are} both hydrogen; and —N (R ¹² ) (R ^{12 ′} ), where R ¹² and R ^{12 ′ are} each hydrogen or alkyl, preferably four of the substituents R ⁵ in ring J are hydrogen, preferably a substituent other than hydrogen is in position 4 of the ring. 9. The compound according to any one of the preceding paragraphs, where q is 0, 1 or 2, preferably, where q is greater than 0, each R ⁶ represents hydrogen and each R ^{6 '} represents hydrogen or alkyl. 10. The compound according to claim 1, where Ar is selected from phenyl, thiophene and furan, preferably phenyl, and where the substituent at position 4 of the phenyl ring is selected from hydrogen, fluoro, chloro, cyano, bromo, iodo, nitro and alkyl, and the rest The four positions of the substituents represent hydrogen. 11. The compound according to any one of the preceding paragraphs, where r is 2, 3 or 5 and each R ⁸ and R ^{8 ′ is} independently selected from hydrogen and alkyl. 12. The compound according to any one of the preceding paragraphs, where B is selected from —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring, having at least one nitrogen atom in the ring, preferably B is —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ and wherein R ¹⁴ , R ¹⁵ , R ¹⁶ and R ^{17 are} independently selected from hydrogen and alkyl . 13. The compound according to any one of the preceding paragraphs, where s is 1 or 2 and R ⁹ represents hydrogen and each R ^{9 '} represents hydrogen or alkyl. 14. The compound according to any one of the preceding paragraphs, where R ^{10 is} selected from 1-naphthyl, 2-naphthyl, indane, 1H-indene, benzocyclobutane, benzocyclobutene, indole, indoline, pyridine, dihydropyridine, octahydropyridine, benzothiophene, benzofuran, benzimidazole , quinoline, quinolone and isoquinoline. 15. The compound according to any one of the preceding paragraphs, where D is selected from fluorine, hydroxy, thiol, alkoxy, aryloxy, alkylthio, acyloxy, cyano, amino, acylamino, —C (O) R ¹¹ and —C (S) R ¹¹ . 16. The compound according to any one of the preceding paragraphs, where X and D are linked together via the linker L, forming a cyclic compound having a structure corresponding to the formula (II)

17. A compound having a structure corresponding to formula (A)

where (A) R ¹ and R ^{1 'are} independently selected from the group consisting of hydrogen, alkyl and acyl; (B) R ^{2 is} selected from the group consisting of hydrogen, alkyl and heteroalkyl; (C) Z ^{1 is} selected from —OC (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) O-; -S (O) ₂ C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) S (O) ₂ -; -N (R ^3e ) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) N (R ^3e ) -; -C (O) N (R ^3d ) -; -N (R ^3d ) C (O) -; -C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -; -C (R ³ ) = C (R ^3a ) -; -C≡C-; -SO ₂ N (R ^3d ) -; -N (R ^3d ) SO ₂ -; -C (R ³ ) (R ^3a ) P (= O) (OR ^3f ) -; and -P (═O) (OR ^3f ) C (R ³ ) (R ^3a ) -; Where (1) each of R ³ , R ^3a , R ^3b and R ^3c , if present, is independently selected from hydrogen, hydroxy, alkoxy, aryloxy, acyloxy, thiol, alkylthio, acylthio, arylthio, amino, alkylamino, acylamino and alkyl; (2) R ^3d , if present, is selected from hydrogen, alkyl and aryl; (3) R ^3e , if present, is selected from hydrogen, alkyl, aryl and acyl; and (4) R ^3f , if present, is selected from hydrogen and alkyl; (D) p is 1 or 2 and each R ⁴ and R ^{4 ′ is} independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, and acylamino; (E) R ^{5 is} selected from hydrogen, hydroxy, chloro, fluoro, —N (R ¹² ) (R ^{12 ′} ), where R ¹² and R ^{12 ′ are} each independently selected from hydrogen and alkyl; (F) q is 0, 1 or 2; where, when q is greater than 0, each R ⁶ and R ^{6 ′ is} independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, and acylamino; (G) R ^{7 is} selected from hydrogen, halogen, —NR ¹³ R ^{13 ′} , alkyl, acyl, alkene, alkyno, cyano, nitro, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; where each R ¹³ and R ¹³ independently selected from hydrogen and alkyl; (H) B is selected from —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring containing at least one atom nitrogen in the ring; where R ¹⁴ , R ¹⁵ , R ¹⁶ and R ^{17 are} independently selected from hydrogen and alkyl; where, in addition, a combination of two or more R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ may optionally combine with the atoms to which they are attached to form a monocyclic or bicyclic ring; (I) R ¹⁰ represents an optionally substituted bicyclic ring selected from 1-naphthyl, 2-naphthyl, indane, 1H-indene, benzocyclobutane, benzocyclobutene, indole, indoline, pyrindine, dihydropyrindine, octahydropyrindine, benzothiophene, benzofuran, benzofuran, benzofuran, benzofuran, benzene quinolone and isoquinoline; and (J) R ^{11 is} selected from the group consisting of amino; alkylamino; -NHOR ¹⁸ , where R ^{18 is} selected from hydrogen and alkyl; —N (R ¹⁹ ) CH ₂ C (O) NH ₂ wherein R ¹⁹ is alkyl; -NHCH ₂ CH ₂ OH; and -N (CH ₃ ) CH ₂ CH ₂ OH; or its optical isomer, diastereomer or enantiomer; its pharmaceutically acceptable salt, hydrate or its biohydrolyzable ester, amide or imide. 18. A pharmaceutical composition comprising: (a) a safe and effective amount of a cyclic peptide analogue according to any one of the preceding claims and (b) a pharmaceutically acceptable excipient. 19. The pharmaceutical composition of claim 18, used to treat a disorder selected from the group consisting of insulin resistance, glucose intolerance, Type II diabetes mellitus, coronary heart disease, high blood pressure, hypertension, dyslipidemia, cancer (for example, endometrial cancer, brain, ovarian cancer, breast cancer, prostate cancer, gall bladder cancer, colon cancer), menstrual abnormalities, hirsutism, infertility, gall bladder disease, limited lung damage, sleep apnea, gout, ost eoarthritis and thromboembolic disease in an animal subject, preferably the disease is a disorder associated with abnormalities in body weight selected from the group consisting of obesity, anorexia and cachexia.