Derivatives and analogs of galanthamine

Abstract

New compounds of general formula I

1 . Compounds of general formula I  
     
       
         
         
             
             
         
       
     
     in which the substituents have the meanings that are explained below: 
 R 1  and R 2  are the same or different and mean:  
 a) hydrogen, F, Cl, Br, I, CN, NC, OH, SH, NO 2 , SO 3 H, PO 3 H, NH 2 , CF 3 , OSO 2  (CH 2 ) n CF 3 , in which n is equal to 0, 1 or 2, —OSO 2 -aryl, —OSO-vinyl or —OSO 2 -ethinyl;  
 b) a low (C 2 -C 6 ), optionally branched, optionally substituted (Ar)alkyl, (Ar)alkoxy, cycloalkyl or cycloalkoxy group;  
 c) an amino group, which optionally is substituted by one or two identical or different low (C 1 -C 6 ), optionally branched, optionally substituted (Ar)alkyl or (Ar)alkylcarbonyl or (Ar)alkoxycarbonyl groups or by a group that is selected from an optionally substituted pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, or homopiperazine radical;  
 d) a —COOH, —COO(Ar)alkyl, —CO-amino group, which optionally is substituted as indicated under c), or a COH(Ar)alkyl group;  
 e) a —(CH 2 )nX (in which X═Br, Cl, F or I), —(CH 2 ) n OH, —(CH 2 ) n CHO, —(CH 2 ) n COOH, —(CH 2 ) n CN, —(CH 2 ) n NC, —(CH) n COalkyl, or —(CH 2 ) n COaryl group, in which n is 1-4;  
 f) a —(CH 2 ) n vinyl, —(CH 2 ) n ethinyl, or —(CH 2 ) n cycloalkyl group in which n is 0, 1 or 2, whereby cycloalkyl is an aliphatic ring with 3 to 7 C atoms;  
 g) a C 3 -C 6 -substituted alkenyl group (optionally substituted with H, F, Br, Cl, CN, CO 2 alkyl, COalkyl, COaryl);  
 h) a C 3 -C 6 -substituted alkinyl group (optionally substituted with H, F, Br, Cl, CN, CO 2 alkyl, COalkyl, COaryl); or  
 i) R 1  and R 2  together mean —CH═CH—CH═CH—, —O(CH 2 ) n O— (n=1 to 3), —CH═CHA 1 -(A 1  is NH, O or S), or —CH 2 CH 2 -A 1  (A 1  is NH, O or S);  
 R 3  has the same meaning as R], especially OH and OCH 3 , or  
 R 2  and R 3  together mean -A 2 (CH 2 ) n A 2 -, in which n is 1 to 3 and substituents A 2  are the same or different and mean NH, O or S;  
 R 4  and R 5  are either  
 a) both hydrogen, or  
 b) one of R 4  and R 5  is hydrogen, an (Ar)alkyl, (Ar)alkenyl or (Ar)alkinyl group, and the other of R 4  and R 5  is 
 i) OR 6 , in which R 6  means hydrogen, a low (C 2 -C 10 , optionally branched or substituted) alkyl group or cycloalkyl group, a C 3 -C 10  substituted silyl group (for example, triethylsilyl, trimethylsilyl, t-butyldimethylsilyl or dimethylphenylsilyl), a C 2 -C 10  alpha-alkoxyalkyl group, for example tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxymethyl, 2-methoxypropyl, ethoxyethyl, phenoxymethyl or 1-phenoxyethyl;  
 ii) O—CS—NHR 6  (thiourethane), in which R 6  has the meanings indicated above under i);  
 iii) O—CO—NHR 7  with the meaning below:  
                     
 iv) O—CO—HR 6 , in which R 6  has the meanings indicated above under i), especially ester with the substitution pattern of amino acids (both enantiomers), such as  
                     
 v) NR 7 R 7 , in which two substituents R 7  are the same or different and mean hydrogen, a low (C 1 -C 4 ), optionally branched, alkyl group or cycloalkyl group, or substituents R 7  together are —(CH 2 ) n —, in which n is 3 to 5;  
 vi) NH—COR 6  (amide), in which R 6  has the meanings indicated above under i);  
 vii) S—R 6 , in which R 6  has the meaning indicated above under i);  
 
 viii) SO n R 8 , in which n is 0, 1 or 2, and in which R 8  is a (C 1 -C 10 ), optionally branched or cyclic, optionally substituted (Ar)alkyl group;  
 G 1 : —(CH 2 ) n —, in which x is 1 or 2;  
 G 2 : —(CH 2 ) y , in which y is 0 to 2;  
 G 3 : —(CH 2 ) n —, in which z is 0 to 3, provided that the sum of x+y+z is at least 2 and at most 4, or in which G 3  is carbonyl or thiocarbonyl, —CH(OH)— or —C(OH)═;  
 W is:  
 a) CR 13 R 14 , in which R 13  means hydrogen and R 14  means —(CH 2 ) n NR 7 R 7 , —CO—NR 7 R 7  or —COOR 7 , in which n is 0 to 2 and R 7  has the above-mentioned meanings, or R 7  and R 7  form a ring via —(CH 2 ) n —, in which n is 3 to 5, whereby substituents R 13  and R 14  can be exchanged;  
 b) N-Phenyl (optionally substituted with fluorine, bromine, chlorine, (C 1 -C 4 ) alkyl, CO 2  alkyl, CN, CONH 2 , or alkoxy) means N-thien-2 or 3-yl, or N-fur-2 or 3-yl or an N-1,3,5-triazinyl, whereby the triazine radical can then be substituted with Cl, OR 6  or NR 7 R 7 , and R 6  or R 7  has the meaning indicated above;  
 c) One of the substituents that is presented below  
                     
  in which I means no bond or —(CH 2 ) n —, whereby n=0 to 3, carbonyl, thiocarbonyl, O, S, —SO— or SO 2 , R 6  has the meanings that are indicated above, and in which, Q is —(CH 2 ) n -M*-(CH 2 ) m , whereby n=0 to 4 and m=0 to 4 and M* means alkinyl, alkenyl, disubstituted phenyl, disubstituted thiophene, disubstituted furan, disubstituted pyrazine, disubstituted pyridazine, a spacer of one of the formulas presented below, a peptide spacer L or a heterocyclic spacer HS of the formulas below,  
                     
  in which R 15  means the side chain of D-, L-, D,L-aminoacids or unnatural amino acids, and for the case of n>1, R 15  in the individual radicals in each case means the same or a different side chain of D-, L-, D,L-amino acids or unnatural amino acids, provided that atom N in addition to Q is connected in each case to groups G2 and G3 of formula I;  
 d) a tricyclic substituent (Tr) that is optionally substituted at least in one place with at least one heterocyclic ring as a ring component and a binding site to a carbon atom of an anellated benzene ring thereof, which is connected via a spacer Q and the nitrogen atom that is adjacent to Q in each case with G 2  and G 3  of the compound of formula I, whereby Q has the meaning that is indicated above under c); or  
 e) —NH—, —O—, —S—, —SO— or —SO 2 —.  
 
   
   
       2 . Compounds of general formula II  
     
       
         
         
             
             
         
       
     
     in which D means N—H, N-alkyl, N-acyl, oxygen or sulfur, and in which substituents R 1  to R 5 , G 1  to G 3  and W have the meanings that are indicated in general formula I.  
   
   
       3 . Compounds of general formula III  
     
       
         
         
             
             
         
       
     
     in which X—R 16  is a substituent, in which X is oxygen or sulfur and R 16  is hydrogen or a low (C 1 -C 10 ), optionally branched, optionally substituted (Ar) alkyl group, and in which substituents R 1  to R 5 , G 1  to G 3  and W have the meanings that are indicated in general formula I.  
   
   
       4 . Compounds of general formula IV  
     
       
         
         
             
             
         
       
     
     in which R 18  and R 19  mean hydrogen, alkyl, aryl or aralkyl, and in which the C atoms that carry substituents R 18  and R 19  are linked to one another via a single bond or a double bond, and in which substituents R 1  to R 5  and G 1  and G 3  have the meanings that are indicated in general formula I, whereby W means CH or N.  
   
   
       5 . Compound according to  claim 1 , in which substituent R 6  means a triethylsilyl, trimethylsilyl, t-butyldimethylsilyl or dimethylphenylsilyl.  
   
   
       6 . Compound according to  claim 1 , in which substituent R 6  means tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxymethyl, (2-methoxypropyl), ethoxyethyl, phenoxymethyl or (1-phenoxyethyl).  
   
   
       7 . Compound according to  claim 1 , in which R 4  is hydrogen, and R 5  is OH, CN, CO 2 -alkyl, CONR a R b , in which Ra is hydrogen, a low (C 1 -C 6 ), optionally branched, cyclic, substituted alkyl group, and R b  is hydrogen, a low (C 1 -C 6 ), optionally branched or substituted alkyl group, or R a +R b  together are —(CH 2 ) n —, in which n means 2 to 6, or —(CH 2 ) n E(CH 2 ) n —, in which E is the same as NH, N-alkyl, O, or S, and n is 0 to 5, aryl (phenyl or naphthyl), or a 6-heterocycle.  
   
   
       8 . Compound according to  claim 7 , in which the 6-heterocycle is imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and substituted variants thereof, imidazolinyl, thiazolinyl or oxazolinyl.  
   
   
       9 . Compound according to  claim 1 , in which R 5  has a meaning other than hydrogen, and R 4  is OH.  
   
   
       10 . Compound according to  claim 1 , in which R 4  and R 5  together are carbonyl (═O), hydrazone (═N—NH—R 9 , ═N—NR 9 R 10 ) or oxime (═N—OR 10 ), in which R 9  is hydrogen, a low (C 1 -C 6 ), optionally branched or cyclic, optionally substituted (Ar)alkyl- or (Ar)alkylcarbonyl-, (Ar)alkylcarbonyloxy group or a sulfonic acid group, such as tosyl or mesyl, and R 10  is hydrogen, a low (C 1 -C 6 ), optionally branched or cyclic, optionally substituted (Ar)alkyl- or (Ar)alkylcarbonyl group, a sulfonic acid group, such as a tosyl group or mesyl group.  
   
   
       11 . Compound according to  claim 1 , in which R 4  and R 5  together are substituents of the type  
     
       
         
         
             
             
         
       
     
     in which Y 1 , Y 2  are the same or different and mean O, S, NH or N—R 9  (free valences are in any case hydrogen), in which R 9  is hydrogen, a low (C 1 -C 6 ), optionally branched or cyclic, optionally substituted (Ar)alkyl- or (Ar) alkylcarbonyl-, (Ar)alkylcarbonyloxy group or a sulfonic acid group, such as tosyl or mesyl.  
   
   
       12 . Compound according to  claim 11 , in which Y 1  is NH and Y 2  is N—R 9 , and in which R 4  and R 5  are connected by —(CH 2 ) n — (n=2, 3, or 4).  
   
   
       13 . Compound according to  claim 1 , in which G 1  and G 2  together or separately mean: 
 —C(R 11 R 12 )—, in which R 11  and R 12  mean hydrogen, OH, a low, optionally branched or cyclic, optionally substituted (Ar)alkyl, aryl, (Ar)alkyloxy or aryloxy group or together an alkylspiro group (C 3 -C 7  spiro ring).    
   
   
       14 . Compound according to  claim 1 , in which G 1  and G 2  together mean  
     
       
         
         
             
             
         
       
     
     in which m is 1 to 7.  
   
   
       15 . Compound according to  claim 1 , in which tricyclic substituent Tr is a condensed benzene ring of general formula  
     
       
         
         
             
             
         
       
     
   
   
       16 . Compound according to  claim 15 , in which ring A is a substituted benzene ring.  
   
   
       17 . Compound according to  claim 15 , in which one of rings B and C is an optionally substituted heterocyclic ring and the other is a substituted ring that can contain one or more heteroatoms in the ring.  
   
   
       18 . Compound according to  claim 15 , in which the benzene ring is substituted in at least one place, whereby these substituents are halogens, such as fluorine and chlorine, halo-C 1 -C 3  alkyl groups, such as trifluoromethyl, C 1 -C 3  alkyl groups, such as methyl, C 1 -C 3  alkoxy groups, such as methoxy, and the hydroxy group, especially a halogen, such as fluorine.  
   
   
       19 . Compound according to  claim 15 , in which the optionally substituted heterocyclic ring B or C is a 4- to 14-membered ring, preferably a 5- to 7-membered ring, especially a 5- to 7-membered, nonaromatic ring, which contains one or two identical or different heteroatoms.  
   
   
       20 . Compound according to  claim 19 , in which at least one heteroatom of the heterocyclic ring (1 to 3 heteroatoms are possible) is nitrogen, oxygen, or sulfur.  
   
   
       21 . Compound according to  claim 20 , in which heterocyclic ring B or C is pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, pyrrolidine, piperidine, hexamethylenimine, tetrahydrofuran, piperazine, morpholine or thiomorpholine.  
   
   
       22 . Compound according to  claim 15 , in which the 5- to 8-membered ring B or C is a 5- to 8-membered heterocyclic or alicyclic ring, or a carbon ring that is substituted at least in one place.  
   
   
       23 . Compound according to  claim 22 , in which the 5- to 8-membered carbon ring is a benzene ring or a saturated or unsaturated ring, for example, benzene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene and cycloheptadiene.  
   
   
       24 . Compound according to  claim 1 , in which tricyclic substituent Tr is a group from one of the formulas that is presented below  
     
       
         
         
             
             
         
       
     
   
   
       25 . Compound according to  claim 1 , in which tricyclic substituent Tr is a group from one of the formulas that is presented below  
     
       
         
         
             
             
         
       
     
   
   
       26 . Compound according to one of  claims 1  to  25   claim 1 , in which Tr is a cyclic or bicyclic hydrocarbon.  
   
   
       27 . Compound according to  claim 26 , in which Tr has one of the formulas below:  
     
       
         
         
             
             
         
       
     
   
   
       28 . Compound according to  claim 1 , in which substituent Tr is substituted at least in one place with R 1 , and R 1  has the meanings indicated in  claim 1 .  
   
   
       29 . Compound according to  claim 1 , in which substituent W is nitrogen and/or substituent G 1  is —(CH 2 ) x —, in which x is equal to 1 or 2 and G 2  means (CH 2 ) y —, in which y is equal to 0 to 2, provided that x+y together mean at least 2 and at most 4.  
   
   
       30 . Compound according to  claim 1 , in which substituents G 1  and G 2  together or separately have the meaning of —CR 11 R 12 —, in which R 11  and R 12  mean hydrogen, hydroxy, a low, optionally branched or cyclic, optionally substituted (Ar)alkyl, aryl, (Ar)alkoxy or aryloxy group.  
   
   
       31 . Compound according to  claim 1 , in which G 1  and G 2  together are an alkylspiro group (C 3 -C 7  spiro ring).  
   
   
       32 . Process for the production of the compounds of  claim 1 , characterized in that the combinatory or parallel-synthesis technology is used, whereby the basic molecule is immobilized by a functional group (linker) in a solid phase, which implements the synthesis of the target compound and then this target compound is separated from the solid phase.  
   
   
       33 . Process according to  claim 32 , wherein the basic molecule is immobilized in the solid phase via a carbon center, a nitrogen center or an oxygen center.  
   
   
       34 . Process according to  claim 32 , wherein —X(CH 2 ) n CO (X═CH 2 , CO, O, S, NH), —X(CH 2 ) n OCO (X═CH 2 , CO, O, S, NH), —XC 6 H 4 CH 2 — (═CH 2 , CO, O, S, NH), THP, or —X(CH 2 ) n Si(alkyl) 2  is used as a functional group (linker).  
   
   
       35 . Process according to  claim 32 , wherein —X(CH 2 ) n CO(X═CH 2 , O, NH, So 0-2 ), —X(CH 2 ) n CS (X═CH 2 , O, NH, SO 0-2 ), X(CH 2 ) n JCO (X═CH 2 , O, NH, So 0-2 ; J=NH, O, S), or XC 6 H 4 CH 2  (X═CH 2 , O, S) is used as a functional group (linker).  
   
   
       36 . Process according to  claim 32  or  33 , wherein —(CH 2 ) n Si(alkyl) 2 -, —C 6 H 4 Si(alkyl) 2 -, —(CH 2 ) n Sn(alkyl) 2 -, —C 6 H 4 Sn(alkyl) 2 , —(CH 2 ) n S, or —C 6 H 4 S is used as a functional group (linker).  
   
   
       37 . A pharmaceutical composition comprising at least one of the compounds of general formulas I, II, III or IV, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle.  
   
   
       38 . (canceled)  
   
   
       39 . Process for the production of pharmaceutical agents, in which at least one of the compounds of general formulas I, II, III or IV is mixed with a pharmaceutically acceptable vehicle and/or formulation adjuvant.