PH26407A - Substituted pyridylmethyl mercapto sulfinyl-or-sulfonyl thienoimidazole derivatives pharmaceutical compositions containing them and their use as inhibitors of gastric acid secretion - Google Patents

Substituted pyridylmethyl mercapto sulfinyl-or-sulfonyl thienoimidazole derivatives pharmaceutical compositions containing them and their use as inhibitors of gastric acid secretion Download PDF

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PH26407A
PH26407A PH36339A PH36339A PH26407A PH 26407 A PH26407 A PH 26407A PH 36339 A PH36339 A PH 36339A PH 36339 A PH36339 A PH 36339A PH 26407 A PH26407 A PH 26407A
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Philippines
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ome
thieno
imidazole
compound
tolerated salts
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PH36339A
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Hans-Jochem Lang
Robert Rippel
Andreas W Herling
Klaus Weidmann
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Hoechst Ag
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Priority claimed from DE19863605395 external-priority patent/DE3605395A1/en
Priority claimed from DE19863623683 external-priority patent/DE3623683A1/en
Priority claimed from DE19873700436 external-priority patent/DE3700436A1/en
Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of PH26407A publication Critical patent/PH26407A/en

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Description

-2e- ¢Asd No.: 45) Igsued: rE 7 c) / \ . R S
T denotes -S-, -S0- or -50,5~, and rl to Rr? have the meanings given in the description, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as inhibitors of gastric acid secretion.
\ , . J 64 0 7 i
Benzimidazole derivatives having an action inhibiting gastric acid secretion are disclosed in, for example,
German Patent A-25 48 340, European Patent A-5129 and
German Patent A-32 40 248. European Patent A-176 308 (Laid open on April 2, 1986) relates to N-substituted benzimidazole derivatives. .
The present invention relates to thienoimidazole deri- vatives of the formula I
R’ 4 7% 8 1 yrs IQ i 's “g? (1) 13 R in which rl rl —=
A represents a) s b) s OF ©) / \ .
R° R
T denotes -S8-, =-SO or =S0,- rt and R% are identical or different and denote hydro- gen, halogen, cyano, nitro, (C,-Cg)-alkyl, (¢,-Cg) hy-
H F hroxyalkyl, (C,-C¢)-alkoxy, -0/-eH_/ ~C, (2£+1-g)" g, preferably trifluoromethyl or (¢,-C,)Fluoralkyl,-0CF,Cl, 0-CF ,-CHFC1, (c,-Cg)-alkylmercapto, (C,-Cg)-alkylsul- oo finyl, (Cc -Ce)- alkylsulfonyl, (C,-Cg)-alkylcarbonyl,
i (C,-Cg)-alkoxycarbonyl, carbamoyl, N-(CrCy)- alkylcarbamoyl, Ny N-di=(C,-C,)-alkylearbamoyl, (C,-Cg)-alkyloarbonyloxys (C4-Cg)-cycloalkyls phenyl, benzyl, phenexy, benzyloxy, anilino,
N-me thylanilino, phenylmercaptoy phenylsulfonyly phenylsulfinyl, sulfamoyl, N-(C,=C,,) -alkylsul= famoyl or N N-di-(C,-C,) -alkylsul famoyl or, if
A is as defined above under (a) or (c), can also together demote = L ya or -CH=CH-CH=CH-4 one CH, group optionally being replaced by 0, S,
S0 or 80,9
R denotes hydrogen, alkanoyl, (¢,~Cg)-alkylcarba- moyl or another physiologically tolerated pit protective group which can be eliminated, pre- ‘ferably in an acid medium and/or under physiole- gicallyconditions, gt and Rr’ are identical or different and denpte hydro- gen or (C=C) -alkyls °, ® RS 9 i : ’ ’ and R® are jdentical or different and denote hydrogen, halogen, (6,-C, p)-alkyly (C=C) al- «Qe - - ~NR¢R! C.=- -
Koxy, =O [en 7 Cc (2841 BF NR*R", (Cy C,,) alkoxy (cy Co) alkyl, (cy 12) alkoxy~-( 1 C,,) alkoxy, (C,=Cyy)-aralkyloxys (C.-C, p)-alkylmexrcap= to, (C,=C, p) -alkyleulfinyl ro (C=C, p)-alkylsul= fonyl, or tv .
R’ and g® together represent (ea, 7 - 1 * ’ 1 "
RT and R are identical or different and denote hy- drogen or (c,-Cp)-alkyl, or t "
R and R together represent -[en, 7, ~ in which one CH, group can be replaced by O, 8, N-(C,~
C,)-alkanoylimine or N-(C,-C,)-alkoxycarbonyl- imino, tf is an integer from 1 to 10, preferably from 1 to by g is 1 to (2f+l), h is U4, 5 or 6, i is 1, 2 or 3s x is 0 or 1, preferably 1, and n is 3 or 4, and to their physiologically tolerated salts. 1H-Thieno/3,4-d/imidazole derivatives of the formula I in which A is as defined above under (b) are preferred,
In addition, compounds of the formula I in which Rr’ re- presents hydrogen are preferred. T is preferably a -S50- groupe. particularly preferred compounds of the formula I are these in which
A is preferably as defined above under (b), - i -s
/ . / . , / . / '
T preferably denotes a -S0- group, rt and 2 are identical or different and denote hydre- gen (cy-C5)-alkyl, halegen, (C,~C),) alkoxy or (C,-Cy) -alkoxycarbonyl,
R’ is as defined above, b 5
R' and R° each denotes hydrogen, and/or g®, rR’, g® and rR’ are identical or different and de- note hydrogen, halogen, -0-/=CH, /, “CoH ors1-6)Fg?
C.-C )- C.-C, )- -C.)= ( 1 3) alkyl ( 1 W alkoxy, benzyloxy or (cy Co) alkoxy-(C,-C,)-alkyl, rR’ preferably representing hydrogen, halogen preferably denoting chlorine or bromine, but es~- pecially preferred compounds of the formula I are those in which
A is preferably as defined above under (b),
T preferably denotes a -50~ group, rt and r® are identical or different and denote hydrogen
C - - . or (Vy C3) alkyl,
R is as defined above, 4 5
R' and R’ each denote hydrogen, g® and g® are identical or different and denote hydrogen, oe chlorine, methyl or ethyl, rR’ denotes hydrogen and/or ?
R denotes hydrogen, -0-/CH, 7 CB oeiy g)Fg (c, Cy)
alkoxy, (C,-C5)-alkyl or benzyloxy.
The following are of particular importance: 2-(2-picolylsul finyl)-1H-thieno/3,4-d/imidazole; } + (s-me thoxy-2-picol ylsulfinyl)-1-thieno/3,-d/inida= goles 2. (lb-me thoxy-3-ne thyl-2-picolyleulfinyl) -1i-thieno [3+4-d/ imidazoles + (me thoxy-3,5-dine thyl-2-picolylsulfinyl)-1f-thieno= [3,4-d/imidazoles 5 3-me thyl-2-picolylaul finyl) -1i-thieno/3, h-d/ imidazole; > (8-me thyl-2-picolylaul finyl)-1H-thieno/3,h-g7 intdazoles 2-( k-me thyl-2-picolylsulfinyl) -1H-thieno/3,k-d/imidazole; 2-( 5-ethyl-2-picolylsulfinyl) -1H-thieno/3,U4-d/ imidazole; 4, 6- aime thyl-2-(5-me thyl-2-picolyleul finyl) ~1i-thiene™ [3y4-d/ imidazole; -(3-ohloro- lms thoxy-2-picolyleulfinyl) -1f-thieno 3-37 imidazole, 2. [B-(242,3:3, 0,185, 5-0ctaflucropentyloxy) -2-picolyieis finyl/-1B- thieno/3,4-d/imidazoles 2-[En(2,2,33sb ly -heptativorobutyloxy) -2-picolyleut finyl) _ 6-dimethyl-10-thieno/3,4-d7inidazoles . y-[R-(2,2,2,- tri f1ucros thyloxy)-2-picolyloul fiuyl/-hybodins= thyl-1H-thieno/3, 4-d/inidazoles s-[h(212,343-totrafluoropropyloxy) 2-picolyleul inyl7-byé- dime thyl-1H-thieno/3,4-g7inidazole; . 7
2-[F-(2,2,3,3, 3-pentafluoropropyloxy) -2-picolylsulfi- nyk/-4,6-dime thyl-10- thieno/3,4-d/ imidazole; 2-/3-methylh-h-(2,2,2-trifluoroethyloxy)-2-picolylsul- finyl/-1H- thieno/3,4-d/imidazole; 2-/5-me thyl-U-(2,2,2-trifluoroethyloxy)-2- picolylsul- finyl/-1H- thieno/3,4-d/imidazole; 4-/3-me thyl-(2,2,3s3,3-pentafluoropropyloxy)-2-picoly= sulfiny)/-1H-thieno/3,4-d/imidazole; 2-/3-me thyl-h-(2,2,3¢3s 4,14, b-heptasluorobutyloxy)-2- picolyleulfinyl-1H-thieno/3,4-g/imidazele; 2-Th-(2,2,2-trifluoroethyloxy)-2-picolylsul finyl/-1f-thieno [34-47 imidazoles 2-/B-(2,2,3,3- tetrafluoropropyloxy)-2-picolyleul finy}/-1i- thieno-/F,4-d/imidazole; 2. [F-(2,2,313, 3-pentatlucropropyloxy) -2-picolyleultinyl/ -1H-thieno/3,4-d/imidazoles
Alkyl and radical s derived therefrom, such as, for exam ple, alkoxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl, aralkyl or alkanoyl, can be straight-chain or branched, (€g-Cy,)-Aryl is, for example, phenyl, naphthyl or bi- : phenylyl, and is preferably phenyl. (C,=Cyq)-Aralkyl is, for example, benzyl or phenethyl, preferably benzyl. A corresponding statement applies to radicals derived therefrom, such as aralkyloxye
Halogen represents fluorine, chlorine, bromine or iodine.
Colore1-¢) eg is a straight-chain or branched fluori= nated alkylradicale.
R’ preferably represents hydrogen, (c,-Y¢)-alkylear- bamoyl or a radical of the formula VI ~(00-0-) (ca p*-0-) v-B (VI) in which p denotes O or 1, aq denotes O or 1, and B de~ notes hydrogen, an acyl radical or an optionally subs- tituted alkyl radical. 11 12
R™" and RC are identical or different and denote hydro- . gen, (C,~Cg)-alkyl, (C5=Cg)-eycloalkyl, (€,=C,,)-aralkyl or (C¢-C,,)-aryle 11
B and RB" can also together represent a -/[CH, 7. chain with r being 3,4 or 5, preferably L, 16 veing possible on one or more of the CH, groups for one hydrogen atom in each case to be replaced by OH, protected OH, amine, acyl- amino and/or halogen. A radical having a substituted -[c8, 7 - chain is preferably a glycosyl radical which is derived from a glycopyranose, glycofuranose or an oligoe- saccharide and is optionally partially or completely protect- ed by protective groups customary in carbohydrate chemistry. “w 8 w=
Both o¢ - and P -glycosidic linkage of the glycosyl radical is possible.
It can be, for example, & glucofuranosyl or glucopy- ranosyl radical which derives from naturally ocecurr- ing .aldotetroses, aldopentoses, afidohexoses, ketopen- toses, deoxyaldoses, aminoaldoses and eligosaccharides such as disaccharides and trisaccharides, as well as their stereoisomers.
These glycosyl radicals are derived, in particular, from natural D- or L- monosaccharides which occur in micro- organisms, plants, animals or humans, such as ribose (Rib), arabinose (Ara), xylose (Xyl), Lyxose (Lyx), al- lose (ALL), altrose (Alt), glucose (GLc), mannose (Man), gulose (Gul), idose (Ido), galactose (Gal), talose(Tal), erythrose (Ery) threose (THr), peicose(Psi), fructose (Fru), sorbose (Sor), tagatose (Tag), xylulose (Xyu), fucose (Fuc), Rhamnose (RHa), olivose (011), oliose(Olo), mycarose (Myc), rhodosamine (RN), N-acetylglucosamine (GLcNAc), N-acetylgAlactosamine (GalNAc), N-acetylmanno= samine (ManNAc) or disaccharides such as maltose (Mal),
Lactose (Lac), cellobiose (Cel), gentiobiose (Gen), N= acetyllactosamine (lacNAc), chitobiose (Chit), B-galacto- pyranosyl-(1-3)-N-acetylgalactosamine and B-galactopyra- nosyl -(1-3)- or -(1-4)-N-acetylglucosamine, as well as their synthetic derivatives such as 2-deoxy-, 2-amino, 2= acetamido- or 2-halogeno-, preferably bromo- or iodo~- sugars.
Protective groups customary in carbohydrate chemistry are particularly understood to be, for example, the
C,~C,o)-acyl protective groups such as (C,~Cg)-alkanoyl (for example acetyl, trichloroacetyl and trifluoroacetyl), benzoyl or p-nitrobenzoyl, as well as optionally modified methyl, methyloxymethyl, benzyl, tetrahydropyranyl, ben=- sylidéne, isopropylidene or trityl group, preference bow ing given here to the acyl protective groups, in particu- : lar the acetyl (Ac) groupe a) Where p and q are O, the radicals preferably have the following meanings:
Wis a bond or denotes =CO-, ~cr}3RM- or -CO- cr 3RM-. B denotes hydrogen (only if W is not a bond), (C,=C,o)-alkyly (C,-C,;)-alkenyls (c=
C,,) cycloalkyl; (Cg-C, ,maryl which is optionally substituted by 1, 2 or 3 jdentical or different radicals from the series comprising (c,-Cy)-alkyl, chlorine, bromine, fluorine, nitro, trifluorome- thyl, (€,-C,)-alkoxy and hydroxyls -(CH,) ~CH(NH)~-
RY? with 8 = 1-93 the acyl radical of an amino acid, or (C,-C¢)-alkyl which is substituted by up to 4 identical or different radicals from the series comprising F, CL or Br.
RY and RH are identical or different and denote hydrogen, (C,~Cg)-alkyl, (C,~Cg)-al- koxy, (C5-Cg)- cycloalkyl, (C,=Cy,)-aralkyl, (Cg=C,,)-aryl pr pyridyl, or p> and gt? to- gether represent =(CH, J» ~/CH,/ 5~ or =[CH, 7¢» in which 1 or 2 CH, groups can be replaced by O.
RY? denotes hydrogen or (c,-C,o)-alkyl. b) Where q is 1, W and B are as defined above under (a). In addition, W can denote -CO-0- and ~-CO=- omcrLR gt3 and gt having the abovementioned meanings. B can also represent hydrogen in the case where W is a bond. c) Where p is 1 and q is Oy ¥ represents a hond er denotesg ~crL3RM™-, > and 1 baving the mean- ings as under (a). B is defined as under (a), but cannot represent the acyl radical of an ami- . no acide In addition, «C0-0-W-B~ can reprewent other nim protective groups of the urethane type which are not embraced by the abovementioned de~ fenition (cf. for example Hubbuch, Kontakte Merck 3/79 14-23; Bullesbach, Kontakte Merck 1/80 23-35)
An optiodally substituted (Cg=Cy op) ~aryl radical Cane above under (a)) is to be understood to be, for example,
: . phenyl, (o-, m=, p-)tolyl, (0-,m-,p-)ethylphenyl, 2- ethyl-tolyl, 4-ethyl-o-tolyl, S-ethyl-m-tolyl, (o=, m- or p-) propylphenyl, 2ppropylphenyl, 2-propyl (o=q m-,p-) tolyl, 4-imopropyl-2,6-xylyl, 3-propyl-k-ethyl- phenyl, (2,3,4-4 24346- or 2,4,5=) trimethylphenyl, (o=o m-,p-) fiuorophenyl, (o-,m= or p~trifluoromethyl)phenyl, :
L-fluoro2,5-xylyl, (244=92,5-2,6-y 3,4- or 3,5-) difYuworo- phenyl, (o-, m- or p=) chlorophenyl, 2-chloro-p-tolyl, (3-, b=, 5- or 6-) chloro tolyl, {-chloro-2-propylphenyl, 2-isopropyl-k-chlorophenyl, hochloro-3,5-xylyl, (243=,24l=y : 245-4 246- or 3,5-) dichlorophenyl, 4-chloro=-3-fluorophe=~ nyl, (3- or 4u)-chloro-2-fluorophenyl, (o-, m= or p-) tri- fluorome thylphenyl, (o-,m- or p-)ethoxyphenyl, (4- or 5-) chloro-2-methoxyphenyl, 2,4-dichloro-(5- or 6-) methyl= phenyl or (0-4 m- or p-) methoxyphenyle (Cc, =C,o)-Alky1 is 4 for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl or their isomeric forma. (€4-C1)-"yeloalksl also includes alkyl-substituted cyc- loaclkyl and bicyclic and polycyclic systems. It is to be understood to include, for example: cyclopropyl, 2= me thylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethyl- cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methyl- cyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentyleyclopentyl,
3-tert-butylcyclopentyl, 2,2~dimethylcyclohexyl, cycloheptyl, cyclononyl, cyclodecyl, norbornyl or adamantyl.
An Acyl radical of an amino acid is to be understood to be, preferably, the radical of an of -amino acid, in particular from the series of naturally occurring ot -amino acids or their antipodes, such as, for exam- ple, H-Gly, H-Ala, H-val, H=Leu, H-Ile, H-Phey, H=Lys,
H-Pro, H-trp, H-Met, H-Ser, HThr, H-Cys, H-Tyr, H-Asn,
E-Gln, H-Asp, H Glu, H-Arg, H-Orn, or the corresponding radicals in the D configuration.
Without confining the subject-matter of the invention to them, a few urethane protective groups R’ = =-C0-0-WB according to the invention may be mentioned hereinafter (C,-C¢) -Alkoxycarbonyl such as Bocj (C4-C; ,)-cycloalkyl- oxycarbonyl such as Mbocg Iboc or Adocy
H.C CH :
H 3 3 > CH3 o_co-
CO : : -CO~
Mboc Iboe Adoe (C50) ,)-cycloalkyl=(C,~Cg) -alkaxycarbonyl such as Adpocy $s
C-0-CO- Adpoc t
CH
(C¢=C, )-aryl-(C,-Cq)-alkoxycarbonyl such as Z, Fmoc or Bpoc, ® _ . CH 1 3
CH,-0-CO~ ¢ - Qu =CO~ 1 ’ CH : 3
Fmoc Bpoc substituted 2Z radicals such as Moc, Ddz and Z (p-N6,) oC,
CH y > . - - - -— -— sod Heo, 0~CO- 0-CO ’
Moc Dds and modified Z Badicals such as Pyoc and their radi- cals derived from 2-and 3-picoline, which can be substi~ tuted as indicated above for (Cg-Cy,)-aryle
CH_.-0-CO-
CC) 2
Pyoc
Preferred yim protective groups are those which can be eliminated in the presence of acids, preferably in a pH range of about 1-6 and/or under physiological condi- tions. t . =
It is surprising that compounds of the formula I with R’ = H are much more stable than the corres- ponding compounds with R = H. In particular, they are more stable under acid conditions, as prevail in, for example, the stomach, and in the presence of water. Thus, by specific selecttion of an nye pro- tective group it is possible for those skilled in the art to control the release of the active compounds in such as way that this takes place selectively at the site of action.
Chiral carbon and sulfur atoms which are present where appropriate can exist both in the R and in the S eon~ figuration. In such cases, compounds of the formula
I are in the form of the pure enantiomers or a mix- ture of stereoisomers (such as a mixture of enantiomers and a mixture of diastereomers).
Suitable salts are, in particular, alkali metal and al- kaline earth metal salts and salts with physiologically tolerated amines.
The invention also relates to a process for the prepa- ration of compounds of the formula I, which comprises a) reaction of compounds of the formula II >—— x (11) t rR
: in which A, RY, ® and rR are as defined above, and xt denotes i. & leaving group or i i. -SH, -8 or -50," 4 with compounds of the formula III 7
R rR 8
Z
2 4 i
TO 9 : 5 Rr’ (111) in whiéh RY, R, r®, rR’, g® and r’ are as defined above and x2 in the abovementioned case i. demotes ~SHy~8~ or 50," and in the abovementioned case ii. denotes & leaving group er ‘ b) reaction of compounds of the formula IV ~~ NH, : A (Iv)
SN RE-R® in which A, RY, R® and RB are as defined above, with ’ compounds of the formula V 7 6 4R RS 0 R ~ \ | I, c ~ 8 €C wv) 10 7
RA =-0 's
R in which RY, R, z®, rR’, g8 and R’ are as defined above and r'° represents an esterifying group, and i. if desired, oxidation of (an)-S- groups which are (is present, where appropriate, in compounds of the formula I to (an) -S0- or -50,- groupa(s), ji. if desired, oxidation of (an) -SO0-groups(s) which are (is) present, where appropriate, in compounds of the formula I to (an)-S0,-groups(s), jii. if desired, acylation, alkylation or aralkylation of compounds of the formula I in which Rr denotes hydrogen, and iV. if desired, hydrolysis of compound of the formula
I in which R’ does not denote hydrogen, and
Ve if desired, conversion of compounds of the formula
I into their physiologically tolerated salts. it also being possible for two or more of measure 1i-iv, to be carried out in a sequence different from that indicated. if, in accordance with process variant (a), which is pre- ferred in: this connection, compounds of the fermula II are reacted with compounds of the formula I1I, then x or x2 represents a leaving group which canb be removed nucleophi- lically, such as CL, Br, 1, -0-50,-CHz, -0-805-CF, or -0-50,- (CH, ~pCH;) .
The reaction of a compound of the formula II with a com- pound of the formula III or its salts is carried out in an inert solvent such as, for example, water, methylene chloride, methanol, ethanol, acetone, ethyl acetate, toluene, tetrahydrofuran, acetonitrile, dimethyl- formamide, dimethyl sulfoxide or mixtures of these solvents, advantageously in the presence of an inor- ganic or organic base such as, for example, sodium or potassium hydroxide, carbonate, alkoxide, hydride or amide, ammonia, triethylamine, tributylamine or pyridine, at -20 to +150°C, preferably at 0-80°c.
The compounds of the formula II can be prepared jn analogy to known processes, for example by ring closure of appropriate substituted 243=, 3,4~ or 4,5-diamino- thiophenes of the formula IV defined above with appro- priate sulfur compounds such as carbon disulfide ( for example German Patent A-31 32 167).
The 243=, 3,4k- or k,5-diaminothiophenes required for this purpose are either known from the Literature or can i be prepared in analogy to known processes. They are ob- tained by, for example, reduction of appropriately subs~ tituted aminonitrothiophenes. r° jn the esters of the formula V used in process va- - riant (b) represents an egterifying group, preferably (C,-Cg)- alkyl or benzyl.
The reaction of a compound of the formula IV with a com- pound of the formula V in accordance with process vas riant (b) is carried out in analogy to the procedures described in Preston et al., Benzimidazoles and
Congeneric Tricyclic Compounds, Part I, New York, pages 10-13.
The compounds of the formula I thus obtained can, if
S R denotes hydrogen, be converted into physiologicals ly tolerated salts.
Compounds of the formula I with T = ~S= can, further- * more, be converted into those with T = -S0- or=50,= using suitable oxidizing agents. It is also possible in the same manner to oxidize -S-groups in the substi- tuents gt, B? and r® to rR.
This reaction is carried out in a suitable inert solvent such as, for example, methylene chloride, chloroform, carbon tetrachloride, l,2-dichloroethane, toluene, ethyl acetatep acetic acid, trifluoroacetic acid, water, metha- nol, ethanol or mixtures thereof, at -20°C to + 150°C, oo preferably at -10°C to +40°C.
Examples of suitable oxidizing agents are: hydrogen per- oxide, peracids and peresters, such as peracetic acid, trifluoroperacetic acid, monoperphthalic acid, m~-chloro-~ perbenzoic acid and their esters, ozone, dinitrogen, : tetroxide, iodosobenzene, N-chlorosuccinimide, l-chloro- benzotriazole, sodium hypochlorite, potassium peroxodi- sulfate, t- butyl hypochloriteg tetrabutylammonium perio~ date or permanganate, sodium metaperiodate, salenium dioxide or manganase dioxide, ceric ammonium nitrate, chromic acid, chlorine, bromine diazabicycle/Z.2.2/ octane bromine complex, dioxane dibromide, pyridinium perbromide, sulfuryl chloride, 2-arylsul fonyl-3-aryloxa- giridines, titanium tetraisopropylate/tert.-butyl hydro- : peroxide (where appropriate with the addition of dialkyl esters of (D)- or (L)-tartaric acid and a defined amount of water).
It is Likewise possible to use isolated, where appropriate jmmobilized, oxidizing enzymes or microorganisms as oxi- dizing agents,
The oxidizing agente are used in equimolar amounts, and optionally in a small excess of 5- 10 mol % in the oxi- dation to T = -SO-, or in Larger excess and/or at a high- er reaction temperature when oxidation to T = -50 = is desired :
Compounds of the formula I with R = H can be prepared starting from compounds of the formula IV with »’ = and compounds of the formula V, or by acylation, alkylation or aralkylation of compounds of the formula I with rR’ =
H. The second route will be dealt with in some detail hereinafter.
The acylation, alkylation or aralkylation of compounds i of the formula I is carried out in a manner known per, se using the appropriate acylating agents, alkylating agents or aralkylating agents in a suitable organic solventy as a rule at a temperature be tween-78°C and the boiling point of the reaction mixture, where appro=- priate in the presence of a base. pin protective groups of the formula VI with p = 0, q = 1, W = bond and B = hydrogen can be introduced into com- pounds of the formula I 8’ = Hy, T = 8) by, for example hydroxyalkylation, it being possible to introduce yim protective groups with pH! = r*? = hydrogen in a manner known per se (cf. for example Eur. J. Med. Chem. 15 [19807 5863 J. Med. Chem, 22 /19797 1113) by hydroxy- . methylation with formaldehyde in an organic solvent such as, for example, acetonitrile. The hydroxyalkylation is carried out at a temperature between 0°C and the boiling point of the reaction mixture, where appropriate in the presence of a base such as triethflamine.
Hydroxymethyl compounds of the formula VII : 7 r, R° RC - 20 ro (VIX . 5 : s
Ly OH R 2 can be converted in the manner described in European Patent
A-176308, page 11, into acyl derivatives of the for- mula VIII
Lh pb 8 rt R « X R
CS 1—o J 8——C PP - (VIII)
Ww’ , “2? 1 . 5
CHy~0~W=B R : in which W-B is an acyl radical.
Compounds of the formula I with R’ = H can also be alkyl- ation with reagents of the formula IX 0 "
Halogen-CH,~0-C~WB (1X) such as, for example, chloromethyl pivalate, in a known manner, the corresponding carbonates (W = -CO-0O- or -c0-0-CRY3RM-) being obtained. The reaction ie carried out in the manner described in, for example, European
Patent A-176308, page 12.
Acyl radicals of amino acids are coupled onto compounds of the formula I with R = H in a known manner ( for exam- ple the DCC/HOBt or dialkylphosphinic anshydride method). pio protective groups of the formula VI with p = 0, q = 1 and rR! and Aor RZ = hydrogen are introduced by react- : ing a compound of the formula I (r% =H, T = 8) with 1 to 10 equivalents, preferably 2 to 3 equivalents, of the cor- responding oC -halogenoalkyl ester. The oc- halogenoalkyl esters which are used are obtained from acid halides and aldehydes by known methods (cf. for example J.
Amer. Chem. Soc. 43/1921/ 660; J. Med. Chem. 23/19807 469-474).
Bromoalkyl esters are preferably used. Alternatively, it is possible to treat the anion of a compound of the formula I (rR? = HB, T = 8), which can be obtained from the Latter and NaH, with the ol.= halogenoalkyl esters
It is also possible in place of the oC =- halogenoalkyl esters to use (1-alkylecarbonyloxyalkyl) pyridinium salts which are prepared in analogy to the knwon (l-ayylcar=- bonyloxyalkyl)pyridinium salts (cf. Angew. Chem, Supple 1982, 675-685) from the corresponding acyl halides, al- dehydes and pyridine.
Alkylamino acetals of the formula I in which R repre=~ : sents a radical of the formula VI in which p is 0, q is 1 and W denotes a bond or ~crL3RM, and B has the above- mentioned meaning, are prepared by treating a compound of the abovementioned formula I (R2=H,T=8) in a dipolar ap- rotic solvent such as dimethylformamide, at about 20 to 50°C, preferably at about 25°¢, with about one equiva- lent of NaH. The anion which is thus obtained is then reacted with about one equivalent of a halogeno ether of the formula halogen-CR'! r12.w-B (halogen =chlorine or bromine), the reaction mixture being stirred at about 20
. . J to 50°c, preferably at about 25%, for minutes. The halogeno ethers are known and many &f them are commer- cially available or can be prepared in analogy to known ) compounds. : 5 Urethanes of the formula I in which Rr’ represents a ure- thane protective group of the formula VI (p=1, q=0 and W = bond or car.) are obtained from the sorres- ponding compounds with Rr’ = H by reacting the Latter, where appropriate in the presence of a base such as NaH, in a suitable solvent such as DMH, with esters of fluoro- formic or chloroformic acid of the formula CL(F)-CO-0-WB ‘ (in analogy to the procedure described in European Patent
A-176308, page 12). }
The fluoroformates and chloroformates are known and are often commercially available or can be prepared by known methods.
Aralkyloxycarbonyl and alkoxycarbonyl groups can also . be introduced using the known dicarbonates, which can often be brought, such as di-terte-butyl dicarbonate and dibenzyl dicarbonate. :
Substituted or modified Z groups in which rt and/or at are not hydrogen are prepared by reaction of the corres- ponding unprotected compound of the formula I, if neces- sarry with the assistance of a base, with the appropriate azides or the appropriate carbonates, - 24k =
It is possible to use for acylation of the compounds of the formula I (R = H, T = 8) not only the customary standard conditions (for example acetic anhydride, tri- ethylamine, dimethylaminopyridine) but also other pro- cesses such as, for example, reaction with N-(l-aryl- carbonyloxyalkyl) pyridinium salts (known from Angew.Chem.
Suppl. 1982, 675-685).
To prepare dialkoxy derivatives of the formula I (R° = -crY3r-B in which rH and gt each denotes alkoxy or together denote alkylenedioxy and B denotes Hy T = 8 or
SO) preferably the corresponding compound of the formula
I with rR’ = H is reacted, in the presence of a base, with the appropriate orthoformic esters such as trial- kyl orthoformates. '
Apart from the thienoimidazole derivatives described in the exemplary embodiments, ijt is also possible to obtain according to the invention, for example, the compounds of the general formula I, or their salts, which are com=- piled in Table 1 which follows:
Abbreviations used: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), hexyl (hex), acetyl (Ac), phenyl (Ph), cyclo (c), iso (i).
TA | Heo
Table 1 rR! a 5 ,T=5 RI=H =
R2 fl 2 Rg gs rE R7 OR
HH H H Me HH H
H H H H Me H OMe H
H H H H Me HM OEt H
H H H H Me Me H H
H H H H Me Me OMe H
H H H H Me Me OMe Me
H H H W Me MH H Me
H H H H Me WH Me : H : H H H H H Me Me : H
H H H H H Et H H
H H H H H H Et H
HH H H HH Pr ~~ H
H H H H H H H Pr
H H H H H H H Bu
H H H H H Me DEt H
H H H H H H oPr H
HH H H HH 0Bu H
H H H H H H OHex H
Wo OHH LL Hex
H H H H H Me Me Me
H H H H H H 0- {Pr H
H H H . H H H iPr H
H H H H H H H iPr - 26 -
Mdwpo.
Table, continuation
Rr! nd ,T=5, RY =H =
Re
Rl_ rz pd 0m ns m6 RT RE
H H H H H Cl H H
H H H Hi i H £1 H
H H H H H H H Cl
H H H HH CY HM Me
H H H H H £1 Me H
TH H H H H H Cl Me
H H H H H H Me C
H H H H H Cl ( ) H
HN HH Wow H
GJ)
I
H H H H i Cl OEt H
H fH H H H cl opr H
H HH H H C1 OBu H
Oe.
H H H H H Ch ( J H “N
H H H H H C1 0-(CHp)p-OMe H
H H H HH Me 0-(CHp)p-OMe H
H H H " H H 0-(CHp)p-Ph H
H H H H H H 0-(CHp)3-Ph H
H H H H H H OCHZCF3 H
H H H Ho *M H OCHp(CF2)2CF3 H
Table, continuation
Rr! "3 , Tes, RI=H
N= . RZ
Rl RZ RY RY pS RE RI R8
H H H H H H OCHZCF2CF 3 H
HH H HHH OCHp-CFp-CFpH H
HH Ho H HW Me OCHp-CF3 H
HH H | HW WH OCHCF3 Me
HH H HH C1 DCHCF3 H
HH H HW Me OCHmFCF3 H
Me H H H HW HH CH
Me H H H HH OMe H
Me H H HH Me OMe | Ho
We H H HH Me OMe Me
Me H H HH Me H H
Me H H H H H Me B H
Me H H H HH HH Me
Me HH HW H HH Et
Me H H H HH 0-CHp-Ph H
Me H H HHO 0) H
N
Me H H HoH () H
Me HH H HCH H
Me HH H KH HO H
Me H H HH C1 Me H
\
Table, continuation
Rr? . n ,T=5 R89 =H
RZ
Roe md RA RS RS RT a8
Me MH H HHH OCHyCF3 H
Me H H fl H te H He
Et H H HH HH H
Et H H Ho HH OMe H
Et OH H HH Me Hf H
Et HM H HO OH HH Me i-Pr H H HH HH H 1-Pr H H HO OHH OMe | H t-Pr H H HH HH Me -gh-Me H H HH HH H -GH-te H H HH KH OMe H . g-He H H HH Me H H
H
. gH- He H | H HOH HH Me -GH-Me H H HoH Me oH | He
DMe Me H HOH HH H
OMe Me H H H Me Oe He
OMe Me H H H Me MH H
OMe Me H HH HH Me
OMe Me H HHH OMe H
OMe Me MH HOH OH Me H
: Table, continuation
RY nd ,T=5, RY =H ; =
RZ
RL kz RY Rt RS RS RT RS
OMe Me H H H cl o H © i
OMe Me H H H a H H y OMe Me H H H H H Et
OMe Me H H H Me H He
Me Ac H H H H H Me
Me Ac H H H H OMe H
Me Ac H H H Me Ohle Me
OEt Me H H H H H H
OFr Me H H H Me OMe Me
OEt Me H H H H Me H
OEt Me H H H H H Me :
OEt Me H H H Me H H
OBu Me H H H H H Me } OBu Me H H H Me DMe Me
OMe OMe H H H H H H
OMe OMe H H H H OMe H
OMe OMe H H H He OMe He
OMe OMe H H H Me H H
OMe OMe H H H H Me H
OMe OMe H H H H H Me
OMe OMe H H H H H Et
Table, continuation . ri n-( ,T=5 RI=H
R2
Rl RZ RS ont ps 6 WTR 0
OMe OMe H Ho HC ® H
OMe OMe H H H Cl OMe H
Oe Me H H H C1 Olde H
OMe H H H H H H H
OMe H H H H H Ole ’ H
OMe H H H H Me OMe Me : OMe H H H H H H Me
OMe H H H H M Me H
OMe H H H H Me H H
OMe - C1 H H H H H H
OMe C1 H H H Me OMe Me
OMe C1 H H H H H Me
PhSO, PhSO, HM H H H H H
PhS0, PhSO; H H H Me DMe Me
PhSO, PhSO; HM H H H H Me
NH-Ph H H H H H H H
HH-Ph H H H H Me OMe He
NH-Ph H H H H H H Me
NH-Ph C1 H H H H
NH-Ph © H Me OMe Me
NH-Ph C1 H H H Me
. .
Table, continuation 1 wl ot
A oY ,T=S5,RI=H oy Ren
Rl R2 R3 RY RS R6 R7 RS 0-Ph H H H H H H H 0-Ph H H H H Me OMe : H 0-Ph H H H I H H ‘Me 0-Ph C1 KH H HHH H
Me Me H H H H H Et
Me Me H © WH OH Et H : Me Me H H H Me H | Me
Me Me H H H Me Me Me
Me Me. H : H H a Me H
Me Me H H H Cl OMe H ‘
Me Me H . H H cv H H
Me Me H H H cn oO H
Me Me H H H Cc (0) H
N
Me Me H H H C1 o H
I
Me Me H H H H 0-CH,Ph H
Me Me H H H H -0-CH,-CF3 H
Me Me H H H H -0-CHp-CFCF3 H
We Et H H OH HH H
Me Et H H H Me OMe Me
Me Et H H H H H Me
C1 COOMe H H H H H H
Cs : Loh
LX pow Ld Co Co
Table, continuation
Rr! nd ,T=5, RY =H
S=
RZ
Rl R2 RY RRS RG RT RS
Cl COOMe H HoH Me OMe Me a C1 COOMe H HHH OMe H
Cl CODMe HM WoW OH on "Me
H CONEty H Ho oi HH H
H CONEtp H HoH Me DMe Me
H CONE H WoW MH Me
H CONHp H HH HH H
H CONHp H HH Me De Me
H CONHy M HW HHH Me
H CONHEt H HH HH | H
H CONMEt M Ho 1 Me OMe © Me
H CONHEt H WH HH He
SO;NMep HH H HH HH H
SOpNMep H H H H He Oe He 50,NMe, H H HH HH Me
H H H H H H H H
HH H HOH Me MH H
H OH H Ho HH Me H
H H H H H Me H Me
HN H HOH HH He
HH H Ho HH OMe i
Ho. H H HH Me OMe Me _ sh.
Co Eo ! : i ' Co Po [I
Table, continuation rt "-( ,T=8 RI=q " 2 .
RR RR 5 m6 RT gs
H H H H H H H Et
Me Me H H H H H Ho
Me Me H H H He OMe Me .
He Me H H H H H Me
H H H H H Cl ® Ho
H H H H H H OCH,CF 3 H
H COOEt H H K H H K
H COOEt H HH Me (OMe Me
H COOEt H H H H H Me
COOMe COOMe H H H H H H
COOMe COOMe H H H Me OMe Me
COOMe COOMe HM H H H H Me -(CHp)g~ HM H H HoH H -(CHz)4- H H H- He OMe Me -(CHz)4- H H H R H Me -CHp-0-CHp- MH H H H H H -CHp-0-CHp- H H H Me OMe Me : -CHz-0-CHp- H H WH HH | Me -CHp-$-CHp H H H H H H -CHp-5-CHp- H HW OH Me OMe CH ~CHz-S-CHp- H H H H H Me - 34
A ebb ben i ea Co
Table, continuation } “4 , T=5, RI =H
Re : RRR mb RS RE WB -CHp-50-CHy H H i H H H vo -CHp-SD-CHp- H H H Me OMe Me . con ® -CHp-S0-CHp- H H H He Ml H -CHp-S0-CHp- H H H H H Me -CK=CH- CH=CH- H H H H H H -CH=CH-CH=CH- H H H Me OMe Me -CH=CH-CH=CH- H H KH Ho Me
Table, continuation ad , T=50, R9=H =
Re
RL R23 R® RS RE RJ RS
HH H H Me HH Ho
HH Ho H Me H OMe Ho
HH H H Me HW OEt fr
HH H H Me Me HM | H
H H H H Me Me OMe H
HH H H Me Me OMe Me
HH H H Me HH Me
HH H H Me H Me H
HH H HH Me Me H
HH H HH Et H H
HH H | HW HoH Et H
HH H H HH Pr H
HW H H HHH Pr
HH H HH HH Bu
HH H HH Me DEE H
HH H HN WH oP H
HHH | HW HH OB H
HH H HHH OHex H
HH H HW HHH Hex
H H H H H Me Me Me
HH H HWW 0-tPr H
HH H HHH pr No :
Table, continuation : rR! 2 , T=50, RY =H —
RZ
Rl_ RZ RY Rt RS RE ® RS
H H H H H H H iPr
Cy HH H H HCl H H
H H Ho H H H Cl H
H H H H H H H CY
H H H H H Cl H Me
H H H H H Cl Me H
H H H H H H C1 Me
H H H H H H Me C1
H H H H H a H
N
: t
HH H HH 0 CJ H
N
.
H H H H H 0) NEL H
H H H H H £1 opr H
H HoH : H H £1 OBu H
H H H H H Cl CO) H
N
’
H H H H H C1 0-(CHp)p-OMe H
H H H H H Me 0-(CHp)zOMe HM
H H H H H H 0-(CHz)2-Ph MH
H H H H H H 0-(CHp)3-Ph H
H H KH H H H OCHCF 3 H
H OH H H H H DCHa(CF2)pCF3 H
Table, continuation : rt : "3 ,T=5,R3=H ne
Rl Rr? R3 R* RS RE R7 R8
H H H H H H OCH,CF 5CF 3 H
H H H H H H OCHp-CFp-CFoH HM ' H H H H H Me OCHz-CF3 H
H H H H H H OCH,CF 3 Me
H H H H H C1 OCHpCF3 H
H H H H H Me OCHpCFaCF3 H
Me H H H H H H
Me MH H H H H OMe | H
Me MH H H H Me OMe H
Me H H H H Me OMe Me
Me HM H H H Me H H
Me H H H HH Me H
Me HH H H H H Me
Me H H H H H H Et
Me H H H H H 0-CHp-Ph H
Me H H H H cl 8 H
Y
Me HM H H HO ® H : N bo .
Me H H H H Cl H H
Me HM H H H H. © H
Me H H H H Cl Me H
Me H H H H H OCH,CF3 H oo - 38 - ! i & Fro
1 i ( or [I 4 : i an | jl : bo
Cl : A wil AE - 6¢ -
H : . ON H H H H 30 M0
H 30 H H H H MW INO au i H H H H 3 INO
H H 3M H H H CIV ay WO 9M H H H 3 2n0
H H H H H H 34 *0
Hp 3 H 2K H H H H 3W-H-
H
MW H H H H H H aH
H
: H H a H H H H oH-1D- 9
Ho ay H H H H H 3W-HJ- : 9
H MH H H H H H 3H-HI- ap H H H H H H 4d-}
H 3K0 H H H Ho H dd-d i H H H H H H 4d-y 3H H H H H H H 13
H Ho 9M H H H H 13
H 3HD H H H H Ho 33
H H " H H H HI aH Ha H H H H 3 gl 4 gd gd p84 ct PEER] i" =
H=gd‘0S=1" )53- . ol ! - uotL3leNUL JUOY ‘Byqey
CL wv
A RIGINAL dP . BADOREFT I, . Lo mn
Table, continuation
CR
0-0 , T=50, RY =H =
Re
RI R2 R3 RY RS R67 RS ee ————————— te
OMe Me H H H C1 (J H i
OMe Me H H H Cl H H
OMe Me H H H H H Et
OMe Me H H H Me H Me
Me Ac H H H H H Me
Me Ac H H H H OMe : H
Me Ac HM | HN OH He OMe Me
OEt Me H H H H H | H
OEt Me ~~ H H H Me OMe Me
OEt Me H H H H OMe H
OEt Me H H H H H Me
OEt Me H HH Me H OH
OBut Me H H H H H Me
DBut Me H H H Me Olde He
OMe OMe H H H H H H
OMe OMe H H H H . OMe H
OMe OMe H H H Me OMe Me
OMe OMe H H H Me H H
OMe OMe KR H H H Me H
OMe OMe H H H iH H Me
OMe OMe H H H H H : Et - ho - : /
Lble, continuation rR! nd , T=50, RY =H $ na
Ro R2 Rm RS RS WR
OMe OMe H H H Cl CO) H )
OMe OMe H H H Cc) Ohle H
OMe Me H H H C1 OMe H
OMe H H H H H H H
OMe H H H H H Ole H
OMe H H HH Me Oe Me
OMe H H H H H H Me
OMe H H | H H H Me H
OMe H H H HK He H H
OMe C} H H H H H H
Me CO) H H H Me OMe Me
OMe cr H H H H H Me
PhSO, PhSO; H HW HHH H
PhSOp PhSO2 HK H H Me OMe Me
PhSO, PhSOp HM H HHH Me
NH-Ph H H H H H H H
NH-Ph H H H H Me OMe Me
NK-Ph H H H H H H Me
NH-PH C1 H OHH H
NH-Ph CI H He OMe Me
NH-Ph C H H H Me - kh o-
Table, continuation rR! ‘ "8 , T=50, RY = H =
Re
RI Rg? R3 RY RS R6 Rp? R8 0-Ph H H H H H H H
O-Ph H H H H Me OMe H
O-Ph HM H H H H H Me 0-Ph H H H H H H H
Me Me H H H H H Et
Me Me H H H H Et H
Me Me H ’ H H Me H Me
Me Me H H H Me Me Me . Me Me H H H Cit Me H
Me Me H H H C1 OMe H
He Me H H H (M9) H H
Me Me H H H Cl Cl H
Me Me H H H c O H
N
1 0
He me H H H Cl ( ) H } N 1
Me Me H H H H 0-CHpPh H
Me Me H H H H -0-CH,CF3 H :
He Me H HHH -0-CHp-CFaCF3 MH
He Et H HH H H H
He Et H H H Me OMe Me
Me Et H H H H H Me
C1 COOMe HK H H H H H he
WR Fl
Table, continuation
Rr! § 0d , T=50, RY =H =
R2
Rl R2 R3 RY RS p6 R7 R8
Cl COOMe H H H Me OMe Me
Cl COOMe HM H H. H OMe H
Cl COOMe H H H H H Me
H CONEt, H H H H H H
H CONEt, H H H Me OMe Me
H CONE, H H H H H Me
H CONH, H H H H H H
H CONHp H H H Me OMe Me
H CONHp H H H H H Me :
H CONHEt H . H H H H H
H CONHEt H H H Me OMe : Me
H CONHEt H H H H Ko Me
SO,NMe, H H H H H H © H
SOpNMep H H H H He OMe Me £02NMey H H H H H H Me
H H H H H H H H
H H H H H Me H H
H H H H H H Me H
H H H H H Me H Me
H H H H H H H Me
H H H H H H OMe H
H H H H H He OHe Me
Table, continuation rR) "0 , T=50,R%=H
N=
RC
Rl R2 R3 RY RS gf gr? RB
H H H H HH HH Et
Me Me H "HH HH H
Me Me H H H Me OMe Me
Me Me H H H H H "Me
H H H HW 0 0) H n }
H H H HHH OCHpCF3 H
H ~~ COOEt H H HH HH H
H ~I0Et H HH Me OMe Me
H COOEt H RH HH Me
COOMe COOMe H H H HH H
COOMe COOMe H HH Me OMe Me
COOMe COOMe HM HH HH Me -(CHp)4- H H H HH H -(CHy)4- H ~H H Me OMe Me -(CHz)g - HM H H HH © Me -CHp-0-CHp- H H HH HH H -CHp-0-CHp- HM HH Me OMe Me -CH2-0-CHp- H HH H Ho Me -CHp-S-CHp- H H HHH Ho -CHp-S-CHyp- H HH Me OMe H -CHp-5-CHp- H H HH NH Me co ' - uy
Yable, continuation
Loy | rR! 2 , T=50,R9=H
Re
Rl R2 R3 RY RS R6 n7 R8 -CHz-50-CHp- H HW HH HH H -CHp-50-CHp- H HH Me OMe Me ~CHp-50-CHap- H HH Me H OH -CHp-S0-CHp- H Ho OH HH Me - CH=CH- CH=CH- H H HHH H -CH=CH-CH=CH- H HO OH Me OMe Me ~ -CH=CH-CH=CH- H HH HH | Me
HH H HOH 0 Me Cl
H OH H HH C1 OEt Cl
H H H HH C1 Opr C)
H H H HH C1 DHex Cl
H H H H HW C1 DipPr 0)
HH H | HH C1 OCHzPh cl
HH H HH C1 O(CHp),0Me CI
HH | H H H Cl O(CHp)zPh cl
HH H H MH Cl OCH CF3 C)
HH H H HCl. OCHp(CFp)aCF3 C1
HH H HH Cl OCHpCFpCF3 C1
HH H | HM Cl OCHpCFpCFpH CO)
Me Me H HH Cl OMe Cl
Me He MH HH © OF C1
Table, continuation rR! "8 » T=50, RY =H “~ PN, ts R2
Rl Rr? R3 RY RS Rr6 Rp? R8
Me Me H HH © opr C
Me Me KH HH Cl OHex C)
Me Me HW H HCl oipr C1
Me Me H HH C1 OCHaPh C)
Me Me H HH C1 O(CHy)OMe C1
Me Me H HH Cl D(CHp),Ph C1
Me Me H HH C1 OCHyCF3 C1
Me Me H Ho HCl OCHy(CFp),CF3 C1
Me Mes H HH C1 CCHCFCF3
Me Me H ‘HH C1 OCHaCFoCFH CI
OMe H H CH HC) OMe cl
OMe H H HH © oft c)
OMe H H HH C1 opr C1
OMe HH HH Cl OHex cl
OMe H H H HC ofr cl
OMe H H H HCl OCH Ph 0
OMe H H HH C1 D(CHp) OMe C1
OMe H H HH C1 0(CHp) Ph cl
OMe H H HH C1 OCHuCFy C)
OMe H H HH C1 OCHy(CFp)pCF3 C1
OMe H H Ho ll C1 OCHpFpCF3
OMe H H HoH C1 OCHCFpCFH CI - Wg -
Table, continuation
Rr? nd , T=50, RI =H =
Re
Rl Rr? R3 R® RS R6 R7 R8
Me OMe H H H C1 OMe C1
Me OMe H H H Cl DEt Cl
Me OMe H H H Cl OPr cl
Me OMe H H H Cl OHex Cl
Me OMe H H H C1 0ipr C)
Me OMe H H H Cl OCH,Ph C
He OMe H H H C1 O(CHp) OMe C
Me OMe H H H Cl O(CHp)zPh Cl
Me OMe H H H Cl OCHCF3 C
Me OMe H N H LC) OCHp(CF,),CF3 CI
Me OMe H H H C1 OCH CF,CFy Cl
Me OMe H HH C1 OCHpCFaCFpH CI
OHe OMe H H H Cl OMe C
OMe OMe H H H C1 OFt Cl
Oe OMe H HH C1 OPr Cl
OHe OMe H H H 1 OHex Cl
OHe ome H H HO OiPr 1
OMe OMe H H H Cl OCHzPh 0
OMe OMe M H H C1 D(CHp)o0Me 0
OMe OMe HM H H Cl 0(CHp)oPh C
OMe OMe MH H H C1 OCH;CF3 C
Oe OMe H H H Cl OCHy(CFp),CF3 CI - h7 -
‘
Table, continuation | . rR "0 , T=50, RI =H =
Re
Rl R2 R3 RY RS R6 RJ RS
OMe OMe H HH C1 OCHCFpCF3 C1
OMe OMe H H HCl OCHxCFCFH C€)
H H H H HCl OMe H el H H H H H Cl OEt H
H H H H HC OPr H
HH H H HCl OHex H
H H H H H C1 Oipr CH
H H Ho H H Cl OCHaPh H
HH H HH C1 O(CHp),OMe HM
H H H H HCl O(CHp)zPh H
HH H HH C1 OCHpCFs H
H H H H HCl DCHp(CFp)pCF3 H
H H . H H . H Cl OCHpCFoCF3 H
H H H H HCl OCH) CFpCFoH H
Me Me H H H Cl OMe H
Me Me H H H Cl OEt H
Me Me H H H C1 OPr H
Me Me H H H 1 OHex H
Me Me H H H C1 OiPr H
Me Me H H H a OCHzPh H
Me Me H H HC) O(CHp) OMe H
He Me H H HC O(CHp)zPh H
Table, continuation \
RY
"0 , T=80, RI=H - =
RZ
RI R? R3 RY RS m6 wp R8
Me Me H H H C1 OCH,CF3 H
Me Me H H H C1 OCHp(CFp)2CF3 H
Me Me H H H C1 OCHpCF,CF3 H
Me Me H H H C1 DCHpCFCFoH HM
H OMe H H H C1 OMe H
H OMe H H H C1 DEt H
H OMe H H H ct opr H
H OMe H H H Cl OHex H
H OMe H H H Cl OiPr H
H OMe H H H C1 OCHzPh H
H OMe H H H C1 O(CHp)2OMe H
H OMe H H H C1 D(CHp),Ph H
H OMe H H H CY OCHpCF3 H
H OMe H H H CY OCHa(CF2)aCF3 H
H OMe H H H C1 DCH,CFCF3 H
H OMe H H H C1 OCHpCFpCFaH H
OMe Me H H H a1 OMe H
OMe Me H H H Cl OEt H
OMe Me H H H Cl OPr H
OMe Me H H H Cl OHex H
OMe Me H H H Ct 0iPr H
OMe Me H . H H C1 OCHyPh H
Tal Ch
Lo C=
Table, continuation
Rr! a0 , T=50,RI=H
N= r2
Rl gp? R3 R& RS R6 R7 R8
OMe Me H HH C1 D(CHp),0Me H
OMe Me H HH C1 O(CHp)zPh H
OMe Me H HH Cl OCH,CF3 H
OMe Me H HH C1 OCHp(CFp),CF3 H
OMe Me H HH - C1 OCHXF,CF3 H
OMe Me H HH C1 OCH CFoCFpH H
OMe OMe H H H Cl DMe H
OMe OMe H H HC OEt H
OMe OMe MH HH C1 opr H
OMe OMe H H H 4] DHex H
OMe OMe H H H C1 OiPr H
OMe OMe H HH C1 OCHyPh H
OMe OMe H HH Cl O(CHp)OMe H
OMe OMe H HH C1 0(CHy)aPh H
OMe OMe H H HCl OCHyCF3 H © OMe OMe H HH C1 OCHy(CFp)sCF3 H
OMe OMe H HH C1 OCHiCFpCF3 MH
OMe OMe H HH C1 OCHpCFpCFpH MH
H H H H H Me OMe C1
HH H H H Me DEt cl
H H H H HH He opr C)
H H H : H H Me OHex Ql
Table, continuation
Rr! n( , T=50, RI=H
R2 ‘ ' RI Rr? R3 R¢ RS RS R! R8
H H H H H He OiPr C1
H H H H H Me OCH2Ph al
H H H HH Me D(CHp)z0Me CI “H H H H H Me O(CHp)2Ph Cl
H H H H H Me OCH,CF3 C1
H H H H H Me OCH, (CF 2) 2CF 3 c)
H H H H H Me OCHpCFCF3 C1
H H H : H H. Me OCHpCFpCFoH CI
Me Me H HH Me OMe Cl
Me Me H H H Me OEt C1
Me Me H H H Me OPr Ci
Me Me H H H Me DHex C1
Me Me H HH Me oDOiPr cl
Me Me MH HH. Me OCHpPh C)
Me Me H H WH Me D(CHp)0Me C)
Me de H H H Me 0(CHz)2Ph Cl
Me Me H HH Me OCHCF3 CY
Me Me H H H Me OCHa(CF2)oCF3 C1 .
Me Me H H H Me OCHpCFpCF3 cl
Me Me HW HH Me OCHpCFCFK C1
OMe H H H H Me OMe al
OMe H H H H Me OEt Cc)
Table, continuation
Rr! “4 , T=50, RI =
R2
Rl R2 R3 RY RS m6 g7 R8
OMe H H H H Me oPr Cl . OMe H H H H Me OHex Ql
OMe H' MH HH Me OiPr cl -
OMe H H © H H Me OCH,Ph C
OMe H H HH He O(CHp)p0Me (1
OMe H H HH Me D(CHp)pPh 0
OMe H H HH Me OCHyCF3 . Cl
OMe H H HH Me OCHp(CF),CF3 CI
OMe MH H HH Me OCHCFCF3 C1
OMe HH HH Me, OCHCFCFoH C1
Me OMe H | Ho OH Me OMe 3)
Me OMe H HH Me Ot C1
Me OMé H HH Me oOPr Cl
Me OMe H CH H Me OHex a
Co Me OMe H H H He 0iPr 0
Me OMe H HH Me OCHyPh 0
Me OMe H HH Me O(CHp)sOMe C
Me OMe H HH Me O(CHp)oPh C
Me OMe H HH Me OCHyCFg cl
Me OMe H HH Me OCHy(CF),CF3 C1
Me OMe H oo CHW Me OCHaCFpCF3 C1
Me OMe HW HoH Me OCHpCFoCFpH C1
Table, continuation : Rr ul , T=50,RI=H o
RL R2 Rom gs nf wR
OMe OMe H H H Me OMe C1
OMe OMe H H Me OEt. cl
OMe OMe H HH He OPr cl
OMe (Me H H H He OHex C1
OMe OMe H H H Me OiPr cl
OMe OMe H H H Me OCHpPh Cl
OMe OMe H H H Me D(CHp)20Me cl
OMe OMe H H H Me O(CH2)2Ph cl
OMe OMe H H H Me OCH,CF3 Cl
OMe OMe H H H Me OCHp(CFp)oCF3 CI ‘OMe OMe H HH Me OCH) CFCF3 OC)
OMe OMe H H H Me OCHpCFCFoH CI
H H H H H Cl OMe Me
H H H H H Cl OEt Me
H H H H H Cl opr Me
HH H © HH C1 OHex Me
H H H H H Cl OiPr Me
H H H H H Cl OCHPh Me
H OH H H NH C1 O(CHp)zOMe Me
H H H H H C1 O(CHp)2Ph Me
H H H H H C1 OCHpCF3 Me
H H H H H a OCH, (CF2)2CF3 Me - 537 =
Ay Ca
Table, continuation ® , T=50, R9 =H : fe &(
Re rl R2 R3 rR RS r6 rR? RS
HH H HH C1 OCHpCFaCF3 Me
HH H HH C1 OtHCFoCFpH Me © © Me Me = H H H a1 OMe Me he Me H H H C1 OEt Me
Me Me H H H Ci OpPr Me
Me Me H HH Cl OHex te
Me Me HM H HC oer Me
Me Me H HH C1 OCHpPh Me
Me Me H HH Cl O(CHp),OMe Me
Me Me H HH C1 O(CHp)Ph Me
Me Me HM HH Cl OCHCF3 Me
Me Me H HH C1 OCHp(CFp)aCF3 Me
Me Me H HH Cl. OCHiCFpCF3 Me
Me Me H HH C1 OCH) CF,CFoH Me
H OMe H H H C1 Olde Me
H OMe H Ho HC OE Me
H OMe H H HC oer Me
H OMe H HH C1 Oex Me
H OMe H HoH cl ofpr Me
H OMe H H WH C1 OCHpPh Me
H OMe H HH C1 O(CHp) OMe Me
H OMe H | HH C1 O(CHp)oPh Me
Table, continuation
Bg k n-0( ,T=50, RO=H =
RZ
By Rl RZ R3 NU RS R6 rR? RB
H OMe H H H al OCH,CF 3 Me
H OMe H H H cl OCHp(CF2)2CF3 Me
H OMe H H H C1 OCHoCF CF 3 Me
H OMe H H H (A OCHoCFoCFoH Me
OMe OMe H H H a1 OMe Me
OMe OMe H H H 0 OEt Me
OMe OMe H H H ) OPr Me
OMe OMe H H H 0 OHex Me
OMe OMe H H H Cl OiPr Me
OMe OMe H H H 1 OCH2Ph Me
OMe OMe H H H ci O(CHp) 20Me Me
OMe OMe MH H HM Cl O(CHp)2Ph Me
OMe OMe H H H C OCH,CF3 Me
OMe DMe H H H a OCHp(CF2),CF3 Me
OMe OMe ' H H HCl OCH)CFCF3 Me
OMe OMe H H H a1 OCHZCFCFH Me
OEt HM H H H a OMe Me
OEt H H H H a Ott Me
Ott H H H H al OPr Me
Okt H , H H H a OHex Me
Ott H H H H Cl DiPr | Me
Ott H H H H C1 OCHzPh Me ’ - 55 .- ) ' | I
Table, continuation o! a -3( , T=50, R9 = H y=
Rr?
RL RZ 3 R' RS RS 7 R8
OEt NH H H H C1 O(CHp),0Me Me ® OEt H H H H Cl O(CHp)Ph Me
OEt H H H H Cl OCHyCF3 Me
OEt H H H H C1 OCHp(CFp),CF3 Me
Et MH H HoH oo OCH,CFCF3 Me
OEt H H H H Cl OCHCF,CFH Me
H H H _H H Me OMe Br
H H H H H Me OFt Br
H H H H H Me OCH,Ph Br
H H H H H Me OCH,CFj Br
Me H ~ H H H Me OMe Br
Me Me H H H Me OMe Br
Me Me HN HH Me Ot Br
Me Me H H H Me OipPr Br
H OMe H HH Me OMe Br
H OMe MH H H Me OFt Br
H OMe H H H Mn 0iPr Br
H OMe H H H Me OCHaPh Br
H OMe H H H Me OCH,CF, Br
H OMe H H H Me OCHaCH,CFy Br
Me OMe H H H Me OMe Br
OMe OMe H H H oe Me OMe 8r
{ oo Table, continuation \ 21 . "3 , T=50, RI =H
N=
RE
RI Rr? R3 RY RS R67 RS
OMe OMe H H H He OPr Br wo OMe OMe H H H Me OCHyPh Br
OMe OMe HM H H Me OCHpCF3 Br
H H H H H C1 OMe Br
H H H H H Cl OPr Br
H H H H H Cl OCHyPh Br
Me H H H H Br OEt Br
Me Me H H H Br OMe Br
Me Me H H H Br OCHPh Br
H OMe H H H Br OMe al
H OMe H H H Br OPr Ci
H OMe H H H Br OCHzPh 0
H OMe H H H Br OCHCF3 Cl
Me OMe H H H Br OMe Cl
OMe OMe H H H Br OMe C) : OMe OMe H H H Br DEt C
H H H HH Br OCHpPh H
H H H HH Br OCHpCF3 H
H H H H H Br OCHpCF2CF3 H
Me Me H H H Br Ole H
Me Me H H H Br OCHzPh H
OMe H H H H Br OMe HM
,
Table, continuation
Rr? "0 , T=50, R9 = H
FE
RZ
Rl R2 R3 Ré RS R6 _R7 R8
DMe H H H H Br OCHpPh H a OMe H H H H Br OCH,CF3 H
OMe H H H H Br OCHpCF,CF3. H
Me OMe H H H Br Ott H
Me OMe H H H Br OCHpCFoCF3 H
OMe OMe H H H Br OMe H
OMe OMe H H H Br OEt . H
OMe OMe H HW HW Br Or H oo OMe OMe H H HBr OCHPh CW
OMe OMe H H H 8r OCH,CF3 H
H H H H H Br OMe Me i H H H H H Br Ott Me
HHH H HBr Oibr Me
H H H H H Br OCHpPh Me
H H H H H Br OCHCFpCF3 Me
Me Me H HH Br OMe Me
Me Me H H H Br DEt Me
Me Me H H H Br OCHCF3 Me
Me Me H H H Br OCHCF 2CF3 Me
OMe H H H H Br OMe Me
OMe H H H H Br DiPr Me
OMe H H H H Br OCHZPh Me
Table, continuation ’ rR? «7 , T=50, RI =H
R2
RlL__R2__ R3 R® RS m6 R7 RE
OMe H H H H Br OCH,CF3 Me { OMe H H H H Br OMe Me
OMe OMe H H H Br OMe Me
OMe OMe MH H H Br OCHpPh Me
H H CH 0Ac H H Me OMe C0)
H H CHp0AC H H Me OEt Cl
H H CHp0AC H H Me OCHpPh Cl
H H CH 0AC H H Me OCH,CF3 Cl
Me H CH,0AC HH Me OMe C)
Me Me CHz0Ac H H Me OMe Cl
Me Me CHZ0AC H H Me OEt Cl
Me Me CHp0AC H H Me OiPr Cl
H OMe CHp0Ac H H - Me OMe (
H OMe CHpOAc H H Me OEt Cl
H ode CHaDAc HH Me Ofpr cl
Co H OMe CH OAC H H Me OCHaPh 0
H OMe CHpOAc H H Me OCH CF3 Cl
H OMe CHpDAC H H Me OCHCHpCF3 CI
Me OMe CHz0Ac H H Me OMe C
OMe OMe CHzO0Ac H H Me OMe Cl
OMe OMe CHo0Ac H | H He Opr C1
OMe OMe CH20Ac H H Me OCHZPh a - 59 =
Pode BET 0 oo |i et | pee
:
Table, continuation
R! "0 , T=50, R=} )=
RZ
Rl Rr R3 RY RS RE R? R8
OMe OMe CH OAc HH Me OCHyCF; Cl
H H CHa0Ac H H Cl OMe Cc
H H CHpOAc H HC opr 0
H H CHz0Ac HH C1 OCHyph Cc
Me H CH20Ac H H © Of C1
Me Me CHz0AC H H Cl OMe C1
Me Me CHp0Ac H Wooo OCHpPh 0
H OMe CHDAc H HC OMe c
H OMe CHpDAc H H C) opr cr
H OMe CHpDAC HH C1 OCHpPh cl
H OMe CHz0Ac HH C1 OCHpCF3 ())
Me OMe CHy0Ac H H C1 OMe cl :
Me OMe CHpDAC HH C1 OMe a
OMe OMe CHpDAc H H C' OEt Cl
H H CH0AC H H Cl OCHzPh H
HH CHz0AC HH C1 OCHCF3 Ho
H H CHp0Ac H H Cl OCHpCFCF3 H
Me Me CH20AC” H H a OMe H
Me Me CHz0Ac H H Cl OCH Ph H : OMe H CHp0AC H HCl OMe H
OMe H CH 0AC HH Cl OCH,Ph H
Table, continuation rR “2 , T=50, RI =H
R2
RI Rr? R3 RY RS R6 RI? RS
OMe H CHp0AC H H C1 OCHpCF,CF3 H “ Me OMe CHp0Ac H H CY DOEt Ho
Me OMe CHyDAc H H Cl OCH CFCF3 H
OMe OMe CH20Ac H H Cl OMe H
OMe OMe CHpDAc H H Cl OFt H
OMe OMe CHpDAc H H Cl Oifr H
OMe OMe CHpDAc H H C1 OCHpPh H
OMe OMe CHpDAC H H C1 OCH,CF3 H
H H CHp0AC H H Cl OMe Me
H H CHp0AC H H . Cl OEt Me
H H CHyDAC H H C1 OiPr Me a H H CH,0Ac H H C1 OCH Ph Me
H H CHp0AC H H Cl OCHpCF,CF3 Me
Me Me CHo0AC H H C1 OMe Me
Me Me CH 0AC H H Cl Oft Me
He Me CHp0AC H H Cl OCH, CF3 Me
Me Me CHp0AC H H Cl OCH CFpCF3 Me
Ode H CH20Ac H H 0 OMe . Me
OMe H CHpDAC H H Cl oipr Mes
OMe H CHpDAc H H Cl OCHpPh Me
OMe H CHp0AC H H C1 OCH CF3 Me
OMe Me CH,0AC H H C1 OMe Me
Table, continuation 26407 vv
Rr! # "0 » T=50,R9 = y we
Rl RZ R3 R* RS gS R7 R8
OMe OMe CHpDAc | HH C1 OMe Me
OMe OMe CHpOAc HH Cl OCHpPh Me
OMe OMe CHpOAc HH Cl Dir cl
OMe OMe CHpOAc HH Cl OCHPh el
OMe OMe CHpDAc HH C1 OCHsCFj 0 y HH CH, OAc HH Me OMe Me
H H CH20Ac HH Me OCHpPh Me
Me Me CH,DAC > H H Me OMe Me :
Me Me CH,DAc HH Me OCHpCF3. Me
OMe H - CHa0Ac H H Me (Me Me
OMe H CHz0Ac H H Me Cpr Me
OMe Me CH,DAc HH Me OMe Me
OMe Me CHp0Ac H H Me O(CHp)p0Me Me
OMe OMe CHp0Ac H H He OMe Me
OMe OMe CHpDAc HH tle OCH,CF; Me
H H CH, DAC HH C1 OMe Ho
H H CHp0Ac H NH Cl Ot H
H H CH,0Ac H HC opr H
OMe OMe CHyDAc HH C1 OCHpCFg Me
HH CH,0Ac HHH Me H
Me H CHZ0AC HHH iPr H - 62, - oo es CL
Table, continuation
R! 2 , T=50, RY =H =
RC
"4 Rl R2 R3 rR4 RS rE rR? RB
Me Me CHp0Ac H H H Me H
Me Me CHo0AC H H Me iPr H
OMe H CH, DAC HHH Me H
OMe H CHy0Ac H H He Me H
OMe H CHp0AC H H Me iPr H
OMe Me CHoOAC H H Me Me H ; OMe OMe CHp0Ac : H H H Me H
OMe OMe ~~ CH2DAc H H Me Me H
OMe OMe CHp0Ac H H H Me Me
H H CHp0AC H H He Me Me
H H CH0Ac H H Cl Me H
Me Me CH20Ac H H Me Me Me
Me Me CHo0AC H H Ci Me H
Me Me CHo0Ac H H H Me ci
OMe H + CHpDAc H H Me Me . Me
OMe H CH20Ac H H a Me H
OMe OMe CH20AC H H Me Me Me
Ome OMe CHp0Ac H H a Me H
OMe OMe CHo0Ac H H He Et Me
H H CH0Ac H H Cc Me Ql
H H CHoDAC H H ) Me Me
H H CHo0AC H K Cl Et Me - 63 ~ i * !
Table, continuation
Rr! a8 , T=50, RY =H y= rR? : RL RZ g3 | RRS p6 pg? RB
Me Me CHyOAc HH Cl Me Me
Et Et CHp0Ac HH Me Me CI
OMe H CHp0AC HO OH C1 we 0
OMe H CH0Ac H H a He Me
OMe Me CHo0Ac H H Me Me ci
OMe OMe CH0Ac H H Ci He Me
OMe OMe CHz0Ac H H Me Me a
OEt OEt CHoOAc HH Me Me 0
HH CHz0AC Ho OH Me 2 @) H : Me Me CH,0Ac HOH Me XY H
OMe H CH20Ac H H Me -N H
COEt H CHp0Ac HOH OH oNMep Me
OMe OMe CHpDAC HH CHy -NMep H
OEt DOEt CHyDAc HOH OH hme Me
Me H CH20AC HH C1 sl H
Me Me CHyDAC HOH 0 hme, H
OMe H CHp0AC HOH Ql hme H
OMe OMe CHpOAC HOH C1 ome, H
OMe OMe CHy0Ac HH sl, H o - 6h Z
Sow «
- §9 = 9 13 €402H00 3 H H ovo(€Ha)HI H H 13 YdlHio aN H H ovo(EHIIHI H H 13 WO MW HH 2vO(EHIIHI HH 13 MM) Nn H H ava(EHI)HI H H. 12 ( N- on H H ovo%HI 130 130 a Or 3 HH WOH) WO WO 13 ( N- 13 H H SY0%HI 30 2HO 12 Zan 13 HH | 2v0%HI H 20 3n ZapN- 13 H H vaHI H 3W0 12 { I) H H 2v0%HI H 130 12 Cy 19 H H 3v0ZHI H YdZHIO bo] ZapN- 19 H H 3V0SHI H 30 19 Oh 13 H H 2¥0%H) 3M 3H
EHD ZapN- 12 H H JVO2HI H 13 12 { (3 H H av¥02H) Ho MW 13 ZapN- 1D H H IY0%H) H H gd LY qy GY pd cd 24 1d 24 =
H=gd ‘0S=1"° =v io i] : uotLlenuiLiuod “ayqe ) (rm ~
BAD ORIGINAL P) :
A
Table, continuation }
Rr! «2 , T=50, RI =H
R2
Rl Rr? R3 R& RS R6 RJ R8
Me H CH(CH3)OAc H H Me OMe Cl
Me Me CH(CH3)0Ac H H Me OMe Cl
Me Me CH(CH3)0Ac "HH Me OEt cl
Me Me CH(CH3)0Ac H HH Me OiPr Cl
H OMe CH(CH3)DAc H H Me DMe cl
H OMe CH(CH3)OAc "H H Me OFt Cl / H OMe CH(CH3)DAc H He Me OfPr Cl : H OMe CH(CH3)0AC H H Me OCH,Ph a
H OMe CH(CH3)OAc H H Me OCHpCF3 cl
H OMe CH(CH3)DAc HH Me OCHCHCF3 CQ
Me OMe CH( CH3)OAc H- HH Me OMe cl
OMe OMe CH(CH3)OAc H H Me OMe Cl
OMe DMe CH(CH3)0Ac H H Me Opr 0)
OMe OMe CH(CH3)DAc H H Me OCHpPh Cl
OMe OMe CH(CH3)OAc H H Me DCHiCF3 cr
HoH CH(CH3)0Ac HH Cl DMe 0
HH CH(CH3)0Ac WOH oC opr 0
HH CH(CH3)0Ac H HH C1 OCHPh C1
Me H CH(CH3)0Ac H HC DOft Cl
Me Me CH(CH3)0Ac H H C) OMe oc
Me Me CH(CH3)OAc H H C1 OCHaPh C
H OMe CH(CH3)OAc HH C1 Ode oo f, oo | - 66 - oo
Lo
Table, continuation
Rr 2 , T=50, RI =H
RZ
Rl R? R3 RY RS RS 7 RS
H OMe CH(CH3)OAc H H cl Or Cl
H OMe CH(CH3)OAc H H C1 OCHzPh C lo H OMe CH(CH3)0Ac H H Cl OCHpCF3 cl Co
Me OMe CH(CH3)OAc HM H Cl Oe cl
OMe OMe CH(CH3)OAc H H Cl OMe Cl be OMe OMe CH(CH3)OAc H H Cl Ot Cl
H H CH(CH3)OAc H H Cl OCHyPh H
H H CH(CH3)0Ac H H £1 OCHpCF3 H
H H CH(CH3)0Ac H H C1 OCHaCFCF3 H
Me Me CH(CH3)OAc H H Cl OMe H
Me Me CH(CH3)0Ac H H Cl OCHzPh H . OMe H CH(CH3)0Ac H H Cl OMe H
OMe H CH(CH3)DAc H H Cl OCH2Ph H : OMe H CH(CH3)0Ac H H Cl OCH,CF3 H
OMe H CH(CH3)OAc WH C1 OCH CFpCF3 HM
Me OMe CH(CH3)OAc H H Cl Oft H
Me OMe CH(CH3)DAc H H C1 OCHpCFCF3 H
OMe OMe CH(CH3)OAc _H H Cl OMe H , OMe Oe CH(CH3)0Ac H H C1 OEt H
OMe OMe CH(CH3)DAc H H Cl OiPr H
OMe OMe CH(CH3)OAc H H Cl OCHpPh RH
OMe OMe CH(CH3)DAc H H Cl OCH CF3 H
Cer -
Table, continuation rR? «2 , T=50, RY =H 2
Rl R2 R3 RY" RS R6 RT _R8
HH CH(CH3)OAC HH Cl OMe Me & H H CH(CH3)0Ac H HC Ot Me
H H CH(CH3)DAc H H C1 Oifr Me
H H CH(CH3)0Ac H H C1 OCHpPh Me
H H CH(CH3)0Ac H H C} OCH[2CF2CF3 Me
Me Me CH(CH3)0Ac HH C1 OMe Me
Me Me CH(CH3)OAc H HCl Oft Me
Me Me CH(CH3)0Ac H H C1 OCHpCF3 Me
Me Me CH(CH3)0AC H H Cl OCH) CFpCF3 Me
OMe H CH(CH3)0Ac HH C1 OMe Me
OMe H "CH(CH3)0Ac HH Cl oipr Me
OMe H CH(CH3)0Ac H H Cl OCHzPh Me
OMe H: CH(CH3)DAc H H €1 OCHpCF3 Me
OMe Me CH(CH3)OAc H HC OMe Me
OMe OMe CH(CH3)OAc HH C1 DMe Me
OMe OMe CH(CH3)OAc H H C1 OCHpPh Me : OMe OMe CH(CH3)DAc HH C1 Oipr C1
OMe OMe CH(CH3)OAc H H Cl OCHPh Cl
OMe OMe CH(CH3)OAc HH C1 OCHpCFg Cl
H H CH(CH3)DAc H H Me DMe Me
H H CH(CH3)DAc H H Me OCHyPh Me
Me Me CH(CH3)OAc H H Me OMe Me f ’ CL.
Table, continuation
Rr)
A "0 , T=50, R9=H y=
Re
RI R? R3 RY RS a6 Ww RS
Me Me CH(CH3)DAC H H Me OCHpCF3 Me ® OMe H CH(CH3)DAc H H Me OMe Me ; OMe H CH(CH3)0Ac H H Me OPr Me
OMe Me CH(CH3)0Ac H H Me OMe Me
OMe Me CH(CH3)0DAc H H Me O(CH2)20Me Me
OMe OMe CH(CH3)0Ac H H He OMe Me
OMe OMe CH(CH3)OAc | H H tle DCHpCF3 Me
H H CH(CH3)0Ac H H £1 OMe H
H H CH(CH3)0Ac H H CY OEt H
H H CH(CH3)DAc H H Cl OiPr H
OMe OMe CH(CH3)OAc H H Cl OCHpCF3 Me
H H CH(CH3)0Ac H H H Me Ho
Me H' CH(CH3)OAc HW HH iPr H
Me Me CH(CH3)0Ac H H Me Me H
Me Me CH(CH3)OAc HH Me iPr H
OMe H CH(CH3)0Ac H H H Me H
OMe H CH(CH3)DAC HOH Me Me H
OMe H CH(CH3)0Ac H H Me iPr H
OMe Me CH(CH3)OAc H H Me Me H
OMe OMe CH(CH3)OAc H H H Me H
OMe OMe CH(CH3)DAc H H Me Me. H - 69 ~- ® Co i
Table, continuation .
Rr! . "0 , T=50, RY = H
Y=
RZ , rl R2 R3 RY RS r6 Rr? R8
OMe OMe CH(CH3)DAc HOH OH He Me
HoH CH(CH3)0Ac HH Me Me Me
HH CH(CH3)0Ac HH Cl Me He
Me Me CH(CH3)0Ac H H He Me Me
Me Me CH(CH3)OAc HH Cl Me H
Me Me CH(CH3)0Ac HO HH He C!
OMe H CH(CH3)0AC HH Me Me | Me
OMe H CH(CH3)0Ac HH Cl Me H : OMe OMe CH(CH3)OAc HH He Me Me
OMe OMe CH(CH3)OAc HH Cl Me H
OMe OMe CH(CH3)OAc H KH Me Et Me
HH CH(CH3)0Ac HH Cl Me cl
HH CH(CH3)0Ac HOH C0) Me Me
HH CH(CH3)0Ac H HCl Et Me
Me Me CH(CH3)OAc Ho OH C1 Me Me
Et Et CH(CH3)OAc HH He Me 0)
OMe H CH(CH3)0Ac Ho HC) Me Cl
OMe H CH(CHM3)0Ac HH C1 Me Me
OMe Me CH(CH3)OAc HH Me Me Co
OMe OMe CH(CH3)0Ac H H C1 Me Me
OMe OMe CH(CH3)OAc HH He Me C
DEt OEt CH(CH3)OAc CH HH Me Me C1
Table, continuation : : rR! nL , T=50, RY =H = . Rp?
Rl RZ__ 3 RI RS p6_ Rp’ RS
Hoo CH(CH3)0AC HH Me (J) I “ Me Me CH(CH3)DAc HoH He WH ) H
Oe CH(CH3)0AC Hoon Me N ) H
DEt HM CH(CH3)0AC Ho HH -NMep Me
OMe OMe CH(CH3)OAc HH CH -NMep I
OEt OEt CH(CH3)OAc Ho OH WH -NMep Me
Me H CH(CH3)0AC Ho WC A) H
Me Me CH(CH3)OAc HH Cl -MMep H
DMe H CH(CH3)0AC HOH C1 -NMep H i OMe OMe CH(CH3)DAc Ho OH Cl -NMep H .
OMe OMe CH(CH3)OAc HN HC a ) H
HH CH(CH3)OAc HH Cl -NMep Soo
He CH(CM3)0Ac Woon Cl +) Cl \.
Et H CH(CH3)DAC Ho OH Cl -NMep CH; 7 .
Me Me CH(CH3)DAc HH CO +) Cl
OMe MH CH(CH3)0AC HOH C1 -NMep C1
Table, continuation . rR! a0 T=50,RO=H \=
Re rl R? R3 pd RS RE rR! R8 OCHPh H CH(CH3)0AC HW HO +] ol ye oEt H CH(CH3)OAc H H a - ) C1 :
OMe H CH(CH3)0AC H H C1 -NMep Me oMe HM CH(CH3)0Ac H H C1 NMez a
OMe OMe CH(CH3)OAc OH H Cc {i ) 0) i : OMe OMe CH(CH3)0Ac H H Cc +) Me
OEt OEt CH(CH3)OAc H H Me N ) (3
H H CH(CH3)-0-CO- [CH2]aCH3 H H Me OMe Ci p H H " H H Me OEt C1
H Ho " H H Me OCHoPh a ! an
H H " H H Me OCHpCF3 a
Me H " H H Me OMe al
Me Me " H H He OMe cl :
Me Me " H H Me DEL . C1
Me Me " H H Me O4Pr C1
H OMe " H H Me OMe 0)
H OMe " : H H Me OEt OQ
H OMe wo H- MH Me OiPr C1
H OMe " HW MH Me OCHPh C)
Table, continuation : Rr! ul , T=50,RI=H
R2
Rl Rr? R3 RO RS RE RT RB
H OMe CH(CH3)-0-CO-[CHz]4CH3 H H Me OCH,CF3 C)
H OMe " H H Me OCHpCHpCF3 C wv Me OMe " H H He Me CQ
DMe OMe " H H He OMe Cl
OMe OMe " H H Me Opr C1 : © OMe OMe " H H Me OCHzPh C
OMe OMe . H H Me OCHpCF3 Cl
H H " H H Cl OMe | cl
H H " H H cl OPr Cl
H H " H H Cl OCHzPh Cl
Me H " H H Cl OEt Cl
Me Me " H H Cl OMe Cl
Me Me: " H H Cl OCHzPh C1
H OMe " H H Cl OMe Cl
H OMe =" H H Cl OPr C
H OMe " H H C1 OCHpPh cn
H OMe " H H C1 OCH,CF3 cl
Me OMe " H H Cl OMe Cl
OMe OMe " H H 0) OMe C)
OMe OMe " H H cl OEt C)
H H " H H Cl OCHpPh H
H H " H H Cl OCHpCF3 H
Table, continuation {
R1 "2 , T=50, RY =H \=
R2
Rl RZ R3 R% gS RS RI RE
WH CH(CH3)-0-CO-[CHpJqCH3 HH C1 OCHpCFCF3 H
Me Me n HH C1 OMe H ten Me Me " H H C1 OCHpPh H
OMe H " HW HCl OMe H
OMe H woo MW HC) OCHzPh H
OMe H " WH C1 OCHECF3 HM
OMe H " WH C1 OCHpCFpCF3 HM
Me OMe " WoW oO OE H
Me OMe " HH C1 OCHxCFpCF3 H
OMe OMe " WH Cl OMe H
OMe OMe " WH C1 DE H
OMe OMe " HW HC OiPr H
OMe OMe " HH Cl OCHaPh H
OMe OMe " WH Cl OCHpCF3 H
HoH " HH Cl OMe Me
HoH " HW OH C1 OE Me
HoH " HN HCl OiPr Me
HoH " HW HCl OCHpPh Me
HoH " HH C1 OCHpCFCF3 Me
Me Me n HW HCl OMe Me
Me Me n HW OH CO OE Me
Me Me " HW HCl OCHyCF3 Me -
A .
Table, continuation \ ot . nd , T=50, RY =H o >
Re
Rl rz RY R* RS RS ®7, RS
Me Me CH(CH3)-0-CD-(Cliz)4CH3 H H Cl OCHpCFCF3 Me
OMe H " H H Cl OMe Me ¢ OMe HM n MH £1 Oipr Me
OMe H " H H Cl OCHyPh Me
OMe H " WM Cl OCHzCF3 Me
OMe Me " H H C1 OMe Me
Wr OMe OMe h H I Cl OMe Me
OMe OMe " HH C1 OCHaPh Me
OMe OMe " WH Cl OiPr - cl
OMe OMe " H H Cl. OCHaPh 0
OMe OMe " H N Cl OCHpCF3 (3
HoH Co" HH He OMe Me +
H H " H H Me OCHyPh Me
Me Me " H H Me OMe Me
Mo Me © % H H Me OCHCF3 Me q OHe H " H H He DMe Me
OMe HW " H H Me Opr Me } ” OMe Me " H H He OMe Me vo OMe Me " NH Me DO(CHp) (Me Me
OMe OMe " H H Me Me . Me
OMe OMe " H H Me OCH CF 3 He
H H " H H Cl OMe H t
: i»
Table, continuation - rR! os , T=50, R9 = H y=
R2
Rl RZ R3 RY" RS m6 m7 m8 "HH CH(CH3)-0-CO-(CHp)eCHz HH C1 OFt H
H H " H H cl 0iPr H 0 OMe OMe " H H Cl OCH CF3 H
H H " H H H Me H
Me H " H H H iPr H
Me Me " H H H Me H
Me Me " H H Me iPr "
OMe H " H H H Me H
OMe H " H H Me Me ~~ H - OMe H " H H Me iPr CH
OMe Me " H H Me Me H
OMe OMe " H HoH Me OH
OMe OMe " H H Me Me H
OMe OMe " H H H Me Me .
H H " H H Me Me Me
H H " H H Cl Me H-
Me Me " H H Me Me Me
Me Me " H H C1 Me H. ! | Me Me " H H H i Me . Ci
OMe H " HH Me Me Me
OMe H " HW HCl Me H
OMe OMe " H H Me Me Me
Table, continuation . rl 0-2 7 =150, RO =H _ a
Rl RZ R3 R& RS RE R/ R8
OMe OMe CH(CH3)-0-CO-(CHz)4CH3 H H cl Me H
OMe OMe " H H Me Et Me
H H " H H C1 Me (i
HH " HW 0H Cl Me Me
H H n H H C1 ft Me
Me Me " H H Cl Me Me
Et Et " H H Me Me BE
OMe H " HW HCl Me oo
OMe H " H H C1 Me Me
OMe Me " H H Me Me (
OMe OMe " H H C1 Me Me .DMe OMe " H H Me Me C1
OEt OFt. “ H H Me Me C1
H H " H H Me ) H
Me Me " H H Me a, H
OMe H " H H Me 0 H
Oft H " H H H -NMey Me
OMe OMe ~~" HH CH -NMep H
Ott OEt " H H H -NMe2 Me - 77 - ¥. sl Co ! Co ; ,
Table, continuation | :
R! n= , T=50,R9=H y=
RZ rl RZ R3 RA RS nb n’ R8
Me HM CH(CH3)-0-CO- (CHp)4CH3 H H C) 10 H
M- Me " H H Cl -HMe H
OMe MH " H H Cl -NMep H
OMe OMe " H H Cl -NMep H
OMe OMe " H H Cl HW ) Ho
H H " H H Cl -WMep C)
Me WH " H H cr NO) Cl
Et HM " H i" C1 -NMey CH3
Me Me " | HOH © () Cl
OMe HM: " H H Cl -NMep C1
OCHoPh H " H H Cl iJ Cl
DEt H " : H H cr -N C)
OMe WH " Ho OH Cl -NMep Me
OMe H - " H H C1 NMep Cl
OMe OMe " H H Cl X' ) C)
OMe OMe n HOH Cl 7) Me - 78 -
Geb Co a 1 . i : y , | | er [
Table, continuation
Rr! "0 , T=250, RY = H $=
RZ
RL RZ R3 RY" RS R6_ R? R8
OEt OEt CH(CH3)-0-CO-(CHp)4CH3 HH Me +) Cl
HH CH(Pr)OAc HH Me OMe C)
H H " H WH Me OE oC
H Hoo HH Me OCHpPh C
H H " H HW Me OCHpCF3 Cl
Me H " HH. He OMe C1
Me Me on H H Me OMe C1
Me Me " HH Me OEt | Cl
Me Me " H H Me 0iPr Cl
H OMe " HH Me OMe C
H OMe " HH Me OF Cl
H OMe " H WH Me OiPr a)
H OMe u H HH Me OCHpPh Cl
H OMe " H MH Me OCH,CF3 CQ
H OMe . " H MH Me OCHpCHoCF3 Cl
Me OMe " HH Me OMe Cl
OMe OMe HH Me OMe 0)
OMe OMe " H tH Me Opr C1
OMe OMe " H H Me OCH2Ph Cl
OMe DMe " H H Me OCH,CF3 a
HH n WH Cl OMe Cl
H H n HH Cl opr 0) - 7% - 0 vy
Table, continuation r! «2 , T=50, RO =H
RC
Rl Rr? A R¢ RS RS R7 R8
HoH CH(Pr)OAC HH C1 OCHpPh C)
Me HK n HH C1 OEt | Cl
Me Me u HH Cl OMe cl
Me Me " HH C1 OCHpPh C1
CH OMe " HH C1 OMe Ci
H OMe " HW HCl OP C
H OMe " HH C1 OCHzPh c)
H OMe " H HC OCHCF3 cl
Me OMe " H H C1 OMe Cl
OMe OMe " H H Cl OMe ct
OMe DMe n HW HCl OE 0
HH n HH C1 DCHPh M
HH " HH C1 OCHCF3 H
HoH " WH C1 OCHCFCF3 H
Me Me " HW HCl OMe H : Me Me " HH C1 OCHPh Ho
OMe HM " HH C1 OMe H : OMe H " | HH C1 OCHgPh H
OMe HM m | HH C1 OCHCF3 H
OMe H n HH C1 OCHCFpCF3 MH
Me OMe n H HC Okt H
Me OMe " HH C1 OCHCFpCF3 H _ 80 -
Ew oo } Table, continuation
R sl , T=50, RI =H
N= ,
R2
RI RC R3 RY RS RE R7 RB
OMe OMe CH(Pr)OAc H H Cl OMe H : OMe OMe " H H Cl OEt H
OMe OMe " H H Cl OiPr H
OMe OMe " H H C1 OCHyPh H
OMe OMe " H H Cl OCHpCF3 H
H H " H H Cl OMe Me
H H " H H Cy OEt Me
H H " H H C1 0OiPr Me
H H " H H C1 OCH2Ph Me
H H " | H H Cl OCHCF,CF3 Me
Me Me " HH C1 OMe Me
Me Me " H H a OEt Me
Me Me " H H Cl OCH CFy Me
Me Me " H H C1 OCH,CF,CF3 Me
OMe H H H C1 OMe Me
OMe H " HH Cl OfPr Me
OMe MH " H H Cl OCHaPh Me
OMe H " H H Cl OCHpCF3 Me
OMe H " H H 1 OMe Me
OMe H " H H C1 OMe Me
OMe OMe " H H Cl OCHaPh Me
OMe OMe " H H Cl DiPr CH - 8 - | i
Co
! t
Table, continuation
Rr , T=50,RI=H
N=
R2
RI R? R3 R& RS RE R7 RS
OMe OMe CH(Pr)DAc H H Cl OCHzPh Ci
OMe OMe " : HH C1 OCHCF3 CQ
H H " H H Me OMe Me
H H " H H Me OCH,Ph Me
Me Me " H H Me OMe Me
Me Me " H H Me OCH,CF 3 Me
OMe H " H H Me OMe Me
OMe H " H H Me Opr | Me
OMe Me " H H Me OMe Me
OMe Me " H H Me O(CHp) 20Me Me
OMe OMe " H H Me OMe Me
OMe OMe " H H Me OCH2CF 3 Me
H H " H H 0) OMe H
H H " H H C1 OEt . H
H H " H H C1 0iPr H
OMe OMe " H H C1 OCHpCF3 H
H H " H H H Me H
Me H " H H H iPr H
Me Me " H H H He H
Me Me " H H Me iPr H : OMe H " H H H Me H
OMe H " H H Me Me H _ 87 - | co
I
Table, continuation
Rr 0-4 , T=50, RY = H
Ra
Rl RZ R3 RY RS RE R R8
OMe H CH(Pr)DAC H H He iPr H
OMe Me : " H H Me Me H
OMe OMe " H H H Me H
OMe OMe Y H H Me He H
OMe OMe " H HH Me Me
H H " H H Me He He
HH “ HH Cl Me H
Me Me " H H Me He Me
Me Me " H H 1 Me H
Me Me " H H H Me Cl
OMe H " H H He Me Me
OMe H " H H a) Me H
OMe OMe. " H H Me Me Me
OMe OMe " H H a Me H
OMe OMe ~~" H H Me Et Me
H H " H H Cl te Cl
H H " H H C1 Me Me
H H " H H a1 Et He
Me Me Y H H Ql Me Me
Et Et " H H Me Me Cl
OMe H " H H a Me C1
OMe H n HH Cl Me Me - 83 i
Po : . x i
Table, continuation r1 _— , T=50, RI =H \=
R2
Rl Rr? R3 R¥ RS R6 R? R8
OMe Me CH(Pr)OAc H H Me Me cl
OMe OMe " H H a1 Me Me
OMe OMe " H H Me Me Cl
OEt OFt " H H Me Me Cl
H H " H H Me 4) H
Me Me n HOH Me aD, H
OMe H " H H Me A ) H
OEt H ". H H H -NMe Me
OMe OMe " H H CH -NMey H
OEt OFt " H H H -NMeo Me
Me H H HCO AY H \
Me Me " H H ct -NMe H
OMe - H “ H H Cl -NMep H
OMe OMe " H H Cl -NMep H
OMe OMe " H H C1 A) H
HoH " Ho OH C1 -NMep 3)
Me H ", H H C) A) Cl \ - 84 /- ee
CL
Table, continuation
RY : ow L( , T=50, R9=H = re
Rl RZ R3 R¢ R5 RGR? R8
Et HM CH(Pr)OAC _ H H C1 -NMep CH
Me Me " HOH oC {) Cl
OMe H " H H Cl -NMep C1
OCHzPh H " H HC () cl
OEt H " H H cr ) C)
OMe H K HH Cl -NMep Me
OMe H " H H Cl -NMep C)
OMe OMe " H H - C1 -§ ) C1
OMe OMe " CH H cl +) © Me
OEt OFt n H H Me A ) C)
H H COp-CH(Me)OAc H H Me OMe cl
H H " H H Me OFt C)
H H " H H Me OCHpPh C)
H H " H H Me OCHCF3 C
Me H " H H Me OMe C1
Me Me om H H Me OMe 8]
Me Me " H H Me OEt C1
Me Me " H H Me OiPr [3] - 85 - i +
B
;
Table, continuation ’ ~ Rr1 - nd , T=50, RI =H
RES rl RZ R3 Ré RS Rb R7 __R8
H OMe COp-CH(Me)OAc HH He OMe Cl
H OMe " H H Me OEt C)
H OMe " H H Me 0iPr Cl
H OMe " H H Me OCHpPh C)
H OMe " H H Me OCHpCF3 C1
H OMe " H H Me OCHpCHaCF3 C
Me OMe " H H Me OMe C1
OMe OMe " H H Me OMe Cl . OMe OMe " H H Me Opr Cl
OMe OMe " H H Me OCHoPh Cl
OMe OMe " H H Me OCHpCF3 C)
H H " H H Cl OMe Cl
H H " H H Cl OPr Cl
H H. " H H C1 OCHpPh Cl
Me H " H H Cl Oft Cl :
Me Me ~~" H H Cl OMe Cl
Me Me wo H H Cl OCHaPh Cl
H OMe " H H Cl OMe C)
H OMe " H H cl Opr Cl
H OMe " H H C! OCHpPh el
H OMe " H H Cl OCH CF3 C)
Me OMe " H H Cl OMe Cl
Table, continuation
Rr! . , T=50, RI =H y=
R2 v
RI Rr? R3 pt pS RE R? R8
OMe OMe CO,CH(Me)OAc H H Cl OMe cl
OMe OMe " H H cl OFt cl ' H H " H H C1 OCHpPh H
H H " H H Cl OCHpCF3 H
H H . H H Cl OCHCFCF3 H
Me Me iy H H Cl OMe H
Me Me iL H H Cl OCHpPh Ho
OMe H LE H H Cl OMe H
OMe H " H H C1 OCHyPh H
OMe H " H H C1 OCHpCF3 H
OMe " H H Cl OCH,CFCF3 H
Me OMe " H H C1 OEt H
Me OMe " H H C1 OCH,CF,CF3 H
OMe OMe " H H C1 OMe H
OMe OMe H H Cl Ott H
OMe DMe " H H C1 DiPr H
OMe OMe ” H H C1 OCHzPh H
OMe OMe ; H H Cl OCHpCF3 H
H H " H H Cl OMe Me
H H " H H C1 OE Me
H H " H H C1 OiPr Me
H H Co H H C1 OCHpPh Me
Table, continuation
Rr «2 ,T=150, RY =H re
Rl r2 R3 . r4 RS R6 R7 R8
H H CO,- CH(Me)OAc H H C1 OCH2CFoCF3 Me
Me Me " H H C1 OMe Me
Lo Me Me “ H H Cl OEt Me
Me Me " H H Cl OCH CF 3 Me
Me Me n HW HW C1 OCH) CFCF3 Me
OMe H " HN HCl OMe Me
OMe H " H H C1 0iPr Me
OMe H " H H C1 OCHpPh | Me
OMe H " H H al OCH CF 3 Me
OMe H " H H C1 OMe Me
OMe H " H H Cl OMe Me
OMe OMe " H H C OCH,Ph Me
OMe OMe " H H C1 Oifr Cl
OMe OMe " . H H Ci OCH2Ph 0
OMe OMe " HW HCl OCHpCF3 C)
H H " H H He OMe Me
HH " HH Me OCHzPh Me
Me Me " H H He OMe He
Me Me " HW HW Me OCHpCF3 Me
OMe H " H H Me OMe Me
OMe H " H H Me Opr He
OMe Me vo HH Me OMe Me _
Table, continuation
Rr! «4 , T=50, R =H r2
RL RZ R3 RY RS RS WR R8
OMe Me CO,- CH(Me )0Ac H H Me D(CHp)o0Me Me
OMe OMe " H H Me OMe Me
OMe OMe " H H Me OCHpCF3 Me
H H " H H Cl OMe H
H H " H H cl OEt H
H H " H H a DiPr H
OMe OMe " HH C1 OCHpCF3 H
H H w' H H H Me H
Me H " H H H iPr H
Me Me " H H H Me H
Me Me " H H Me iPr H
OMe H " H H H Me H c H " H H Me Me H
OMe H | “ H H Me iPr H
OMe Me " H H Me Me H
OMe OMe " H H H Me H
OMe OMe " H H Me Me H
OMe OMe " H H H Me Me
H H " H H Me Me . Me < HoH " HH C1 Me H
Me Me " H H Me Me Me : Me Me " H H Cl Me H 0 : :
Table, continuation . rt nS Tes
N=
RZ
RL_Rr2 RY mt RS RE 7 RS
Me Me CO,-CH(Me)OAc H H H Me Cc)
OMe H " H H Me Me Me be OMe H " H H Cl Me H © OMe OMe Ho OH Me Me Me
OMe OMe “ H H Cl Me H
OMe OMe " H H Me Et Me
H H " H H cr Me C1 :
H H " H H Cl Me Me
H Ho " H H Cl Et © Me
Me Me " H H Cl Me Me
Et Et " H H Me Me cl
OMe H » H H Cl Me Cl
OMe H noo H H Cl Me Me
OMe Me " } H H Me Me Cl
OMe OMe " H H C1 Me . Me
OMe OMe " H H Me Me C \ OEt OFt " H H Me Me 0
H H " H H Me -) H
Me Me " H H Me 0 OH
OMe H " H H Me DY H . oor -
ERGATA ETT nme ne - I
Table, continuation 264 ] 07
GuI( .T=50,RS=H \=
RZ
Rl RZ _®3 RY RS__R6 RI R8
OEt H C0- CH(Me)0Ac H H H -NMe) Me
OMe OMe " H H CHy -HMep H
OEt OEt " HOH OH -NMep Me
Me H " HoH oC A ) H
Me Me " RH H a -NMe) H
OMe H " H H C1 -NMep H
OMe OMe " H H Cl -NMep H
OMe OMe " H H cl -¥ ) H
H H " H H Cl -NMep Cl
Me H " H H a A ) (
NI
Et H " H H C1 -NMep CH3
Me Me " WoW CO +) C1
OMe H " CH H Cl -NMe C ? © OCHzPh H " Wo HO {) C)
OEt HW " H HC x) 0)
OMe H " H H C1 -NMe Me f .
Table, continuation
Rr a , T=50, R9=H = re
Rl R? R3 R& RS R6 KR’ R8
OMe H CO,CH(Me) OAc H H C1 -HMe C1 , OMe OMe n H H C1 A) Cl
OMe OMe " H H C1 +) Me
OEt Okt " H H Me +) Ci
H H CO2-CH(Me)-0- CO-Pent H H Me Ote a)
H H u H H Me OEt C1
H H " H H Me OCH,Ph C1
H H " HH Me OCHpCF3 Cl
Me H " H H Me Olle C1
Me Me " H H Me OMe Cl
Me Me " H H Me DEt Cl
Me Me " H H Me iPr al
HK OMe " H H Me Ote C)
H OMe " H H Me CEt C1
H OMe " . H H Me OiPr C1
H © OMe " H H Me OCHaPh Cl
H OMe " H H Me OCH,CF3 Cl .H CMe " H H Me OCH,CH,CF 3 a)
Me OMe " H H Me OMe Cl.
Pent= n-Penty] oo
Table, continuation
Rr 0-4 ,T=50, RI =H \=
RZ
Rl R? R3 Ré& RS. R6 RY RS
OMe OMe C0p- CH(Me)-0-CO-Pent H H Me OMe C1
OMe OMe " H H Me Opr Cl
OMe OMe " H H Me OCH2Ph cl
OMe OMe " H H Me OCH,CF3 ol
H H " H H Cl OMe Cl
H H " H H Cl OPr C)
H H " H H Cl OCHpPh Cl
Me H " H H C1 OFt C1
Me Me " H H Cl OMe Cl
Me vn " WH C1 OCHzPh Cc
H OMe " H H C1 OMe C)
H OMe “ H H Cl OPr C)
H OMe. " H H C1 DCHzPh C)
H OMe " H H C1 OCH,CF3 0
Me OMe =" H H Cl OMe C
OMe OMe " H HCl OMe C
OMe OMe " HW HCl OE C1
H H " H H C1 OCHpPh H
WH " W H C1 OCHCF3 H
H H " H H C1. DCHpCFaCF3 H
Me Me " KH H 0 OMe H
Pent= n-Pentyl
Table, continuation
Rr 0-0 ,T=50,R =H 3
R2
Rl Rr? R3 RY RS RG RT RS
Me Me C0,-CH(Me)-0-CO-Pent H H Cl OCH2Ph H
OMe H " H H Cl OMe H
OMe H " H H Cl OCHzPh H
OMe H " H H C1 OCHpCF3 H
OMe H “ H H Cl OCH,CFoCF3 H
Me OMe " H H Cl OEt H
Me OMe " H H Cl OCH,CFoCF3 H
OMe OMe " HOH CO OMe H
OMe OMe " H H C1 OEt OH
OMe OMe " H H Cl OiPr H :
OMe OMe " H H Cl OCHpPh H
OMe OMe " H H Cl OCHCF3 H
H H " H H Cl OMe Me
H H ooo H H Cl OEt Me
WH HW H Cl Oibr Me
H H " HH C1 OCHzPh Me
H H " H H Cl OCH CFaCF3 Me -
Me Me " H H a1 OMe Me
Me Me " H Hoo OEt Me
Me Me " H H a OCH,CF3 Me
Me Me " H H C1 OCHaCFCF3 Me
Pentz n-Pentyl
Table, continuation
Rr ‘ "0 , T=50, R9=H
N=
R2
Rl Rr? R3 RY pS RGR’ RS
OMe H CO,-CH(Me)-0-CO-Pent H H Cl OMe Me
OMe H " H H a] 0iPr Me
OMe H " H. H Cl OCHpPh Me : OMe H m WH C1 OCHiCF3 Me
OMe Me’ n H H Cl OMe Me :
OMe OMe " H H C1 OMe Me
OMe OMe " H H Ct OCHpPh Me
OMe OMe " H H Cl OiPr Cl
OMe OMe " H H Cl. OCHpPh Cl
OMe OMe " H H Cl OCHpCF3 Cl
HH " HH Me OMe Me
H H " H H Me OCHpPh Me
Me Me " H H Me OMe Me
Me Me u H H Me OCHpCF3 Me
OMe H | " H H Me OMe Me .
OMe H " H H Me Opr Me
OMe Me " H H Me OMe Me
OMe Me " HH Me O(CHg) OMe Me ‘OMe OMe " H H Me OMe Me
OMe OMe “ H H Me OCHpCF3 Me
CH H " H H Cl OMe H
Pent= n-Penty!
Table, continuation rR! , T=50, RI =H = re
Rl RZ R3 R* RS m6 m7 RE
H H COpCH(Me)-0-CO-Pent H H 0 OEt H
H H y H H C1 OiPr H ho OMe OMe " H H Cl OCHpCF3 H
HoH " Ho WH Me CH
H H " H H H He H
Me H " H H H iPr H
He Me " H H H He ~H
Me Me " H H Me iPr H
OMe H " H H H He H
OMe H " H H Me Me H
OMe H " H H Me iPr H
OMe Me " H H Me Me H
OMe OMe oo H H H Me H
OMe OMe " H H Me Me H
OMe OMe " H H H Me Me
H H " H H Me Me Me
H H " H H Cl Me H
Me Me " H H Me Me Me
Me Me " H H a Me H
Me Me " H H H Me 1
OMe H " H H Me Me Me
Pent= n-Pentyl
Table, continuation rl 0-4 1 =50, R% =H = . Re .
RI ®? R3 R® RS RG RT RS
OMe H C0p- CH(Me)-0-CO-Pent H H al Me H
OMe OMe " H H | Me Me Me
OMe OMe " H H C1 Me H
OMe OMe " H H Me Et Me
H H " H H C1 Me Cl
H H u H H C1 Me Me
H .H " H H cl Et Me
He He " H H Cl Me Me
Et Et " H H Me Me Cl
OMe H " H H Cl Me Cl
OMe H " H H C1 Me Me
OMe Me so H H Me Me a
OMe OMe " H H Cl Me © Me
OMe OMe " H H Me Me Cl
OEt OF " H H Me Me Cl
H H " H H Me +) H
Me Me " HW OH Me i, H
OMe H " H H Me + H
OE H " H H H -NMe Me
Vents n-Penty!
Table, continuation rt wd , T=50, RY =H y= 2
RI R? R3 R RS RE Rr’ R8
OMe OMe CO2-CH(Me)-0-CO-Pent H H CHz -NMep H
OEt Oft " H H H -NMep Me
Me H " H H Cl A J H
Me Me " HH Cl -NMep H
OMe HK " HoH Cl -NMep H , OMe OMe " H H C1 -NMe H
OMe OMe " | H HC A) H
HH " H HCl -NMe Cl
Me H " H H cr -N) cl
Et Ho" HH Cl -NMe CH3
Me Me " H H 0 A) Cl
OMe H " HH Cl -NMep C
OCHpPF © Ho HC +] cl : OEt H " H H C1 -K ) Cl
OMe H " H H Cl -NMe) Me
OMe H " CH HD Ne, cl
Pent= n-Penty] 7
Table, continuation -
Rr 0-2 7=50, RY = H >= rE
Rl RZ R3 R& RS R6 R7 R8
OMe OMe CO,CH(Me)-0-CO-Pent H H C1 0) Cl
OMe OMe " H H C1 - ) Me
OEt OEt " CH H Me +) C)
H H Moc H H Me OMe Ci
H H " H H Me OFt Cl *
H H " H H Me OCH,Ph cl
HH " WH Me OCHCF3 cl
Me H Soon H H Me OMe Cl
Me Me u H H. Me OMe Cl
Me Me " WH Me OEt 0)
Me Me " H H Me 0iPr C1
H OMe " H H Me OMe cl
H OMe " H H Me OFEt Cl
H OMe " H H Me DiPr CH
H OMe " H H Me OCH,Ph Ct
H OMe " HH _ Me OCHCF3 Cl
H OMe " H H Me OCH,CH2CF 3 cl
Me OMe " H H Me OMe C1
OMe OMe " H H Me OMe C1
OMe OMe Ddz H H Me Opr C1
Pent= n-Penty! -"99 -
Co I ——_
: T~~le, continuation rR! : a -( , T=50,R =H j=
Re
Rl R2 R3 RY RS RS gp? Li
OMe OMe Ddz : H H Me OCHpPh Cl
OMe OMe " HH Me OCHyCF3 co
HH " HH Cl OMe Cl
HoH " HH C1 opr Cl
HH " HH C1 0cHyPh 0
Me H " Ho Wo okt 0
Me Me " HH Cl OMe BS
Me Me " CHW C1 OcHpPh C1
H OMe " HH Cl OMe C)
H OMe " HH C1 opr CT
H OMe " HH C1 OCHyPh cl
H OMe " HH Cl DCHyCF3 cl
Me OMe. " H H a OMe 0
OMe OMe " HH C1 OMe C0) © OMe OMe HW HCl OE 0
HH Moc HH C1 OCHyPh H
HH " HH C1 OCH,CF3 Ho
HH " HH Cl OCH)CFpCF3 H
Me Me " . H H a OMe H
Me Me " HH C1 OCHpPh H
OMe H " HH Cl OMe H
OMe H " H H C! OCHyPh H
Table, continuation
R1 0-0 T=50, RI =H = re
Rl R2 R3 Co re RS rb R7 R8
OMe H Moc WH C1 OCHpCF3 H
OMe H n WH C1 DCHpCFCF3 H
Me OMe “ Woon CO OE H
Me OMe " H H C1 OCH,CF CF 3 H
Me OMe " H H C1 OMe H
OMe OMe Y H H a OEt H
OMe OMe " H H 1 OiPr H
OMe OMe " HH C1 OCHzPh H
OMe OMe " HW WH C1 OCHaCF3 H
H H Ddz WH C1 OMe 2
H H " H HC} DOE Me
H H " H WH C1 Oifr Me
H H " H H C1 OCHzPh Me
H H " WH C1 OCHCFCF3 Me
Me Me " H H C) OMe Me
Me Me " H HW C1 DE Me
Me Me " H H a OCHCF 3 Me
Me Me " HH C1 OCH CFaCF3 Me
OMe H " H H C1 Ode Me
OMe H " H HH C1 Oifr Me oe H " H WH C1 DOCHzPh Me
OMe HM " HH C1 OCHaCF3 Me
Table, continuation
Rr 0-0 , T=50, RI =H \=
R2
RL RZ R3 RY RS R6 RT R8
OMe Me Ddz H H C1 Me Me
OMe OMe " H H 0 OMe Me
OMe OMe " H H C1 DCH,Ph Me
OMe OMe Moc H H al 0iPr C1
OMe OMe " H H Cl OCHzPh C0)
OMe OMe " H H C1 OCH,CF3 C1 .
HH u HH Me OMe Me
H H " | H H Me OCH2Ph | Me
Me Me " - H H Me OMe He
Me Me " HH. Me OCHyCF3 Me
OMe H " H H Me Otte Me
OMe H " H H Me Opr Me
OMe Me " H H Me OMe Me
OMe Me " H- H Me O(CHy) 20Me Me
OMe ~ " H H Me OMe Me
OMe DMe " H H He OCHCF 3 Me
NH H " H H Cl OMe H
H H " H H C1 DEt H
H H ro H H C1 OiPr H
OMe OMe Ddz HH C1 OCHaCF3 H
HoH " Ho OHH Me Ho
Table, continuation .
Rr = LT =50, RY =H :
RZ
BRR RRS w6 RT ge
Me H Ddr H H H iPr H
Me Me " H H H Me H
Me Me " H H He iPr H
OMe H " H H H Me H
OMe H " H H Me He H
OMe H " H H Me iPr H : OMe Me " .H H Me Me H
Ode OMe " H H H Me H
OMe OMe " H H Me Me H ,
OMe DMe " H H H Me Me
H H " H H Me Me Me
H H " H H C1 Me "H
Me Me " H H Me Me Me
Me Me " H H Cl He H
Me Me Moc H H H Me ci : OMe H " H H Me - Me Me
OMe H " H H C1 He H
OMe OMe " H H Me Me Me
OMe OMe " H H Cl He H
OMe OMe " H H Me Et Me
H H " H H C1 Me Ql
H H " H H Cl Me Me-
Table, continuation
Rr! os , T=50, RY = H = .
R2
Bow www we wa
H H Moc H H C1 Et Me
Me Me " H H Cl Me Me
Et Et " H H Me Me C1 : OMe H " H H ci Me al
OMe H " HH Cl Me Me
OMe Me " | HH Me Me cl
OMe OMe " HOH C1 Me Me
OMe OMe " H H Me Me Ci
OEt Ott 0dz H H Me Me C1
H H " H H Me +] H , : Me Me " H H Me AY H
OMe H =" H H Me -N ) H
Okt HM " Ho OHH -NMep Me
OMe OMe " H H CH3 -NMep H
Ott Oft " H H H -NMe Me
Me H " H H C1 -N ) H
Me Me " H H ci -NMe H
OMe H " Ho OH C1 -NMep H
OMe OMe " H H Cl -NMe; H
Table, continuation rR? es , T=50, R9=H =
RC
Rl R2 R3 R& RS ROR R8 7
OMe OMe Ddz H H Cl K H
H H “ H H Cl -NMey C1
Me H " H H Cl A ) Cl
A
Et H " H H Cl -NMej CH3
Me Me " H H C1 ) 0
OMe H Moc H H Cl -NMep CY
OCHzPh H " H HC £) a
OEt H " MH H cv -K) C1
OMe H " H H C1 -NMep Me
OMe H " H H © C1 -NMey C1
OMe OMe " H H ar -f ) C1
OMe OMe " H H 0 -{) Me
OEt OFt " i H Me -y ) C1 -- 105 « ih
Co poe TT TT : Table, continuation rR a0 , T=50, RY =H =
RZ
Rl R2 RY mt es 6 RF ®
H H —CH,-0-CO-CH, H H H -0-Cil,- (CF,) 2CF3 H . H H —(H,-0-CO-CH, H H H =0-CH,~ (CF,) 4CF,H H
CH, Hy -CH,-0-CO-CH, H H H —0-Ci,- (CF,) 2F3 H
CHy CH; -CH,~0-CO-CH, H H H =0-Cil,~CF, H
Ci; CHy ~CH,~0-CO-CH, H H H -0-CH,~CF,~CF,H H
CH, Hy ~CH,-0-CO-CH, H H H —0-CH,,~CF,~CF H
H H —CH,-0-CO-CH, H H H -0-CH,=CF, CH,
H H —CH,~0-CO-CH, H H CH, -0-CH,—CF4 H
H H ~CH,~0~CO-CH, H H CHy ~0-CH,~CF,~CF, H
H H ~CH,~0-CO-CH, H H Cy -0-CH,~ (CF,) CF, H
H H ~CH,,~0-CO-CH, H H H -0-CH,~CF, H
H H ~CH,~0-CO-CH H H H ~0-CH,~CF,~CFH H
H H ~CH,,~0-CO-CH; H H H =0~CH,~CF,~CF, H - 106 - 0
Hi bo
The new compounds of the formula I and their salts have valuable pharmacological properties.
They markedly inhibit gastrie acid secretion and, furthermore, have an excellent protective action on the stomach and intestines.
In this context, nprotection of the stomach and in- testines" is defined as the prevention and treatment of gastrointestinal disorders, in particular inflamma- tory gastrointestinal disorders and lesions (such a8, for example, gastric ulcer, duodenal ulcer, gastritis, or irritable stomach related to hyperacidity or drugs) which may be caused by, for example, microorganisms, bacterial toxins, drugs (for example antiinflammatory ‘ and antirheumatic agents), chemicals (for example etha- nol), gastric acid or stress situations.
By reason of their excellent properties, the substituted thienoimidazoles of the formula I and their pharmacolo- gically tolerated salts are outstandingly suitable for use in human and veterinary medicine, peing particular- ly used for the treatment and prophylaxis of disorders of the stomach and intestines andof those disorders based on excessive gastric acid secretion. i
It has been found that also the colonic k*-ATPase enzyme
07 ; if 4 —d (cf. Gustin, Goodman, J. Biol. Chem. 256 /1981/10651- 10656) inhibited in vitro by compounds, which are ob- tained on treatment of the compounds of the formula I with acid (for example with NaOAc/HCl buffer with pH ' 4-5,5). Such conversion products can also be formed during khe in vivo passage of the gastro-inteatinal . tract. The amount of their formation depends on the substitution pattern and the pH value.
The colon-k'-ATPaSE is belieded to be of great influence on the electrolyte balance across the mucosal barrier in the colon. Colon-K'-ATPase inhibitors as those mention- ed above, can therefore influence said equilibrium, and they are therefore useful for treating disease involving a disturbed electrolyte balance. : 15 Therefore, the invention relates also to the use of com- pounds of the formula I, and their acid conversion pro- ’ ducts for treating diarrhea diseases. Examples of such diseases are inflammatory intestinal diseases such as cholera, paratyphoid, tourist diarrhea and other forms of secretory diarrhea but also other intestinal diseases such as ulcerous colitis and regional enteritis.
The invention relates furthermore to conversion products, which are formed on treating of compounds of the formula
I with acid.
Hence the invention furthermore relates to the com- pounds of the formula I according to the invention for use for the treatment and prophylaxis of the abovementioned disorders.
Likewise, the invention comprises the use of the com- pounds according to the invention for the preparation of pharmaceuticals which can be used for the treat- ment and prophylaxis of the abovementioned disorders.
The invention furthermore relates to pharmaceuticals which contain one or more compounds of the general for- mula I and/or their pharmacologically tolerated salts.
The pharmaceuticals are prepared by processes which are known per Be and are familiar to the expert. The pharmacologically effective compounds (= active com- pounds) according to the jpvention are used as pharma- maceuticals either as such or, preferably, in combina- tions with suitable pharmaceutical auxiliaries, in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the content of ac- tive compound advantageously being between 0.1 and 96%.
The auxiliaries which are suitable for the desired phar- maceutical formulations are familiar to the expert en the basis of his knowledge. In addition to solvents,
gel forming agents, suppository bases, tableting auxiliaries and other active compound excipeints : it is possible to use, for example, antioxidants, dispersing agents, emulsifiers, antifoam agents,
S flavors, preservatives, solubilizers or colorants.
The active compounds can be administered orally or parenterally, oral administration being preferred.
In general, it has proven advantageous on oral admi- nistration in human medicine to give a daily dose of the active compound or compounds of about 0.01 to about 20 mg/kg of body weight, where appropriate in the form of several, preferably 1 to 4, individual ad- ministrations, to achieve the desired result. On pa- " renteral administration, it is possible to use similar or (especially on intravenous administration of the active compounds) as a rule lower doses. Lvery expert can easily establish, on the basis of his expert know- oo ledge, the optimal dose and mode of administration of the active compounds required in each case.
If the compounds according to the invention and/or their salts are to be used for the treatment of the abovemen~ tioned disorders, then the pharmaceutical compositions can also contain one or more pharmacologically active ingredients ofother pharmaceuticals groups, such as antacids, for example aluminam hydroxide, magnesium aluminate; tranquilizers such as benzodiazepines, for example diazepam, spasmolytice, such as, for example, bietamiverine and camylofing anticholinergics such as, for example, oxyphencylimine and phencarbamide;
Local anesthetics such as, for example, tetracaine and procaine; and, where appropriate, gastrin antago- nists, enzymes, vitamins or amino acids.
For an oral presentation, the active compounds are mix— ed with the additives customary for this purpose, such as vehicles, stabilizers or jnert diluents, and convert- ed, by customary methods, into suitable forms for adminis- tration, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous alcoholic or oily solutions. Examples of inert excipients which can be used are gum arabic, magnesis, magnesium car- bonate, lactose, glucose or starch, in particular corn starch. This can entail preparation as either dry or moist granules. Examples of suitable oily vehicles or solvents are vegetables and animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds of their physiologically tolerated salts are
“ converted, if desired with the substances customary forthis purpose, such as solubilizers, emulsifiers : or further auxiliaries, into a solution, suspension or emulsion, Examples of suitable solvents for the new active compounds and the corresponding physiolo- gically tolerated salts are: water, physiological saline solutions or alcohols, for example ethanol, propanol or glycerol, as well as sugar solutions, such as glucose or mannitol solutions, or a mixture of the various solvents mentioned,
The examples which follow are intended to illustrate the procedures according to the invention without 1li- miting the invention to the substance mentioned here as representative,
The stated melting and decomposition points have not been corrected or standardized,
Example 1: 2-(4=Methoxy-2-picolylmercapto)-1H-thieno/3,4-d/imida~ zole dihydrochloride i 1.6 g of 2-mercaptothieno/3,4-d/imidazole and 2 g of k methoxypidolyl chloride hydrochloride in 50 ml of etha- nol were heated at 60°C for about one hour and stirred at room temperature for a further 40 hours. After the
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BAD ORIGINAL 0 cooled to 0°C, 0.64 g of 3.chloroperbenzoic acid was : ‘added in portions. The mixture was stirred for about minutes while still cooling, and then 20 ml of sa- turated aqueous sodium bicarbonate solution were add- 5 ed ahd the mixture was stigred at room temperature for a further 10 minutes. After the organic phase had been removed and dried over sodium sulfate, the solvent was removed by distillation, the residue was stirred with a mixture of diisopropyl ether and acetone, and the crys- tals were filtered off and dried.
Colorless crystals, melting point 142-144°C,
Example 4: + (h-Methoxycarbonyl-2-picolylmercapto) -1i-thieno/3, h-d/ : imidazole dihydrochloride .
The title compound was obtained in analogy to the pro- cedure indicated in Example 1 from 2-mercapto~6-metho- xycarbonylthieno/3,l4-d/imidazole and 4-methoxy-2-picolyl- chloride hydrochloride.
Colorless crystals, melting point 210-213%C.
Example 5: 6-Methoxycarbonyl -2-(4-methoxy-2-picolylmercapto)~1H- thieno/3.4-d/ imidazole
The title compound was obtained in analogy to the pro- : - 1s -
cedure indicated in Example 2 from the compound of
Example lt.
Colorless crystals, melting point 156-160°C.
Example 6: ° > (2-picolylmercapto) -1i-thieno/3,4-d7 imidazole di- hydrochloride
The title compound was obtained in analogy to the pro- cedure indicated in Example 1 from 2-picolyl chloride hydrochloride and »_mercapto-1H-thieno/3,4-d/imidazole jin isopropanol as solvent.
Colorless crystals, melting point 154-162°C.
Example 7¢ vo tnoeyoarbonyl--(2-pisolylnercepto) Ji-thieno/S:h-47 imidazole hydrate hydrochloride
The title compound was obtained in analogy to the pro- cedure indicated in Example 6 from >-mercapto-li-metho- xycarbonyl-1Hi-thieno/3,4-g/ inidazole and 2-picolyl chlo- ride hydrochlorides
Colorless crystals, melting point 204-208°C. 20. Example 8:
Sodium salt of 5. (5-me thyl-2-picolylsul finyl) -1H-thienos [34-47 imidazole 0.036 g of sodium hydroxide was dissolved in 15 ml of me-
thanol, and 0.24 g of 2-(5-methyl-2-picolylsulfinyl) -1H-thieno/3,4-d/imidazole was added to the solution which is then stirred at room temperature for 30 minutes.
The solvent was removed by distillation under reduced > pressure and the product was crystallized from ethyl acetate and filtered off.
Colorless crystals, melting point 320°C.
Example 91 2-(5-Methyl-2-picolylsulfonyl)~1H-thieno/3,4-d/imida~- gole
To a two-phase mixture composed of 20 ml of methylene chloride, 20 ml of saturated aqueous sodium carbonate : solution and 1 g of 2-(5-methyl-2-picolylmercapto)~-1H- thieno/3,4-d/imidazole was added dropwise at 0°C a so- lution of 1.34 g of 3-chloroperbenzoic acid in 25 ml . of methylene chloride. The mixture was stirred at O- 50¢ for 30 minutes, the organic phase was separated off and dried over calcium chloride, and the solvent was removed by distillation. The dark residue was pu- rified on silica gel by column chromatography using ethyl acetate/methanol =8:1 as the mobile phase and was crystallized from ethyl acetate. €olorless crystals, melting point 163°C,
Example 10: 2-(4-"ethoxy-2-pyridylme thylsulfinyl)-1H-benzotheino~
© [3,3-d/imidazole a) 3.2 g of anino-2-nttrovense/5_Jthiophene were hydregenated in 100 ml of me thanol under 1 bar and at room temperature in the presence of Raney nickel until the theoretical amount of hydfogen has been absorbed, and the solvent was removed from the fil- trate by distillation under reduced pressure. The resulting 2,3-diaminobenzo/ ©_/ thiophene was with=- out further purification, dissolved in 200 ml of di- chloromethane, 3.56 8 of thiocarbonyldiimidazole were added, and the mixture was allowed to react at room ‘ temperaturd for 48 hours and then the 2-mercapto-lH- venzothieno/2,3-d/inidazole was filtered off.
Crystals, melting point above 230°C. : 15 b) To a mixture of 1 g of 5 mercapto-1i-benzothieno- : [2,3-d/imidazole with 50 ml of isopropanol, 10 ml of water and O.4t g of NaOH was added 0.97 g of Bume thoxy- picolyl chloride hydrochloride, and the mixture was stirred at the reflux temperature for 2 hours and then the solvent was removed by distillation. The residue jas taken up in 40 ml of water, the solution iB extract- ed with ethyl acetate, and the solvent was removed bY distillation, resulting in 5 (l-me thoxy-2-picolylmercap= : to)-1H-benzothieno/3,4-d/ imidazole as a viscous amorphous material. ¢) To a solution of 1 g of 2-(4-methoxy-2-picolyl- mercapto)-1H-benzothieno/Z,3-d/imidazole in 75 ml of dichloromethane at room temperature was added 0.6 g of m-chloroperbenzoic acid and, after stirring for 20 minutes, saturated aqueous sodium bicarbonate solu- lution was added, and the organic phase was separated off. After the solvent had been evaporated off under reduced pressure, crystallization was induced by treat- ment with a little ethyl acetate and diisopropyl ether.
Colorless solid, decomposition above 90°c.
Example ‘lt 3-Yh1oro-l-methoxy-2-picoline-N-oxides
To a solution of sodium methylate, prepared from 0.51 g of sodium and 20 ml of methanol, at -10°C were added 3,5 g of 3, 4-dichloro-2-picoline-N-oxide in 20 ml of an~- hydrous methanol. The mixture was allowed to warm slow- ly to room temperature and was then heated to reflux for 1 hour. The solvent was now removed by distillation un- der reduced pressure, water was added to the residue, the mixture was extracted with dichloromethane, and the solvent was evaporated off.
Colorless crystals from diisopropyl ether, melting point 9% =97°Ca
Example 122 5-Un1 oro-2-hydroxyme thyl- k-me thoxypyridine: 5.8 g of 3-chloro-l-me thoxy-2-picoline-N-oxide were dissolved in 8 ml of glacial acetic acid and, while stirring at 90°c, 14 ml of acetic anhydride were add- ed. The mixture was heated at 110-115°¢C for 2 hours and then cooled to 80°C and 25 ml of methanol were added dropwise. The solvent was then removed bY distillation under reduced pressure, and subsequently 20 ml of water and 8 g of sodium hydroxide were added in small portions to the residue, and this mixture was heated to reflux for 2 hourse After cooling, the mixture was extracted with dichloromethane, the solvent was evaporated off, and the residue 38 induced to crystallize with diethyl ether. solid, melting point 103-105°Ce
Example 13% suChloro-2-chlorome thyl-l-methoxypyridine hydrochlorides
To a mixture of 2.6 g of 3. chloro-2-hydroxyme thyl~l-metho xypyridine and 30 ml of dichloromethane at -10 £0-15°C was added dropwise a golution of 3.5 ml of thionyl chlo~ ride in 25 ml of dichloromethane, and then the mixture was stirred at room temperature for 2 hours. The so0l- vent was evaporated off, and the residue was induced to crystallize with diethyl ether.
: Colorless crystals, melting point 145-146°C.
Example 1h: . a) 3-Acetylamino-4,5-dimethoxycarbonyl-2-nitrothio- phene
The compound was obtained by nitration of 3-acetyl- amino 4,5-dimethoxythiophene with potassium nitrate/ sulfuric acid or with nitric acid.
Crystals, melting point 160 « 165°C. b) 3-Amino-U,S5-dimethoxycarbonyl-2-nitrothiophene
The compound from the preceding example was hydrolysed with methanolic hydrochloric acid.
Crystals, melting point 104 - 107%. c) 2-Mercapto-4,5-dime thoxycarbonyl-thieno/3, 3~d/imida~ zole 2,3-Diamino-4,5-dimethoxycarbonylthiophene (0.02 mol) was obtained from the 3-amino-nitrothiophene derivative described above by hydrogenation with lbar of hydrogen at room temperature with Raney nickel as catalyst. The diamino compound thus obtained was without further puri- fication, stirred with 0.02 mole of thiocarbonyldiimida~ zole in 50 ml of anhydrous dimethylacetamide at room temperature for 2 hours and then at 50°¢c for 1 hour, the ‘solvent was removed by distillation in vacuo, and the rev gidue vas induced to crystallize in isopropanol, cooling in ice. .
Crystals, melting point 95 ~ 97°C.
Example 152 : pthoxyearbonyl-2-(i-methoxy-2-picolylacraapte) Ii" thieno/3,4-d/imidazole
Under nitrogen, 1.k g (5.0 mmol) of 2=( b-me thoxy-2-
Jicolyluercapto)-1i-thieno/3,h-d7 imidazole were dis- solved in 15 ml of anhydrous dimethylformamide, and 270 mg (6 nmol) of a 60% suspension of NaH in oil were added in portions, and the mixture was heated at 30-40°C for 10 minutes. Now at 25°C, 0.5 ml (5 mmol) of ethyl chloroformate (95%) was added, during which the temperature jncrease to about 36°C. 30 minutes later the crystalline product was filtered off with suction and washed twice with diethyl ether.
Melting point 154-156°C (decomposition).
Example 16:
EthoxycarbonyL-2-(h-ne thoxy-2-pieolyleul finyd) mHE" thieno/3,4-d/ imidazole
To 750 mg (2.1 mmol) of 1-e thoxycarbonyl-2-( -methoxy= -2- ico1ylnercapto) -1i-theino/3h-/inidazole in 30 ml of methylene chloride and 25 ml of 0.5 N aqueous sodium bicarbonate solution were added dropwise, with stirring, initially 420 mg (2.1 mmol) and then a fur- ther 210 mg (le 05 mmol) of 3-chloroperbenzoic acid in
CH, CL, The organic phase was dried omer MgSO), and
. concentrated in vacuo, and the residue was crystal=- lized from ethyl acetate.
Melting point 143° (decomposition).
Example 17: 1-Vinyloxycarbonyl-2-(5-methyl-2-picolylmercapto)-1H= thieno/3,4-d/imidazole
In analogy to Example 15 1.5 g of crude product were obtained from 2.1 g (8 mmol) of 2-(5-methyl-2-picolyl- mercapto)-1H-thieno/3,4-d/imidazole and 0.85 g (0.72ml, 8mmol) of vinyl chloroformate andwwere chromatographed on 810, (CH CL ,/ MeOH 50:1). 1.1 g of title compound were obtained by crystallization from diisopropyl ether.
Melting point 78 = 80°C.
Example 18: 1-Vinyloxycarbonyl-2-5-me thyl-2-ficolylsulfinyl)-1H~ thieno/3,4-d7 imidazole
In analogy to Example 16 0.5 (1.5 mmol) of l-vinyloxy- carbonyl-2-(5-methyl-2-picolylmercapto) -1H-thieno/3,k- : -d/- jmidazole was oxidiged witn m-chloroperbenzoic acid but in a 2-phase mixture composed of methylene chloride and aqueous KH_PO/Na HPO, buffer solution (pH= 7.5)s Chromatography on 810, is carried out with
CH_CL,/CH 50H (30:1),
Melting point 162°C
Example 193 -Bonayloxycarhonyl-2-(-methoxy-2-picolylaercapto) _1H-thieno/3,4-d/imidazole 1.4 g (5 mmol) of >. (li-me thoxy-2-picolylmercapto)= 1H-thieno/3,l4-d/imidazole were reacted in analogy to Example 15 with 0.8 ml (5 mmol) of benzyl chloro- formate (90-95%). 2.2 g of oily crude product were obtained and were chro- matographed on silica gel (35 - 79 / with toluene/ ethyl acetate (1:5). The product crystallized from di- ethyl ethers
Melting point 102 = 104°C.
Example 20: Benayloxycarionyl-2=(5-me thyl-2-picolylaercepto) His theino/3, 4-47 imidazole (5th tny1-2-piselylaercapto) -Li-thieno 3 h-g/amider zole was reacted in analogy to Example 19. The DMF were removed by distillation in vacuo, the residue was taken up in CH, CLs and the solution was extratted by shaking with water and dried over MgSO. After concen- tration, the title compound crystallized from ethyl ace- tate.
Melting point 103 = 104°C.
Example 21: ho thosybenzyloycarbonyl)-2=(5-me thyl-2-BieelyES
. mercapto)-1H-thieno/3,4-df imidazole
To 1.3 g (5 mmol) of 2-(5-methyl-2-picolylmercapto)- 1H- theino/3,4-d/imidazole dissolved in 15 ml of an- hydrous DMF were added, under nitrogen , 275 mg (6 6 mmol) of sodium hydride, After the mixture had been heated at 40-50°C for 10 min, at room temperature 1.92 g (7.5 mmol) of lb-methoxybenzyl phenyl carbonate (pre- pared from L-methoxybenzyl alcohol and phenyl chlorofor- mate) were added, and the mixture was heated at 30-40°C for 10 minutes and stirred at room temperature for 1 hour.
The solvent was removed by distillation in vacuo, and water was added to the residue. The oily/resinous pre- cipitate was taken up in CH,CL,, and the solution was dried over MgSO, and the solvent was evaporated off. The residue crystallized from diethyl ether and was recrys- tallized from isopropanol.
Melting point 120-121°C.
Example 22: 1-(4-Methoxybenzyloxycarbonyl)-2-(5-methyl-2-picolyl- sulfinyl)-1H-thieno/3,4-d/ imidazole 850 mg (2 mmol) of the title compound from Example 21 were dissolved in 50 ml of CH,CL,» and 50 ml of aqueous
Na HPO, /KH_PO, buffer solution (pH 7.5; 7.4 ml of
KH PO, solution (45.35 g/L) + 42.5 ml of Na HPO, solu-~ tion (59.6 g/L) were added. While stirring vigorously at room temperature, 500 mg (2.5 mmol) of m-chloroper- ’
benzoic acid dissolved in CH,CL, were added dropwise.
The organic phase was dried over MgSO, and concentrat- ed, and the residue was chromatographed on silica gel using ethyl acetate. The title compound crystallized from isopropanol.
Melting point 119-120°C.
Example 23: tert. -Butoxycarbonyl-2-(5-nethyl-2-picolyluercapto)” 1H-thieno/3,k4-d/imidazole 2 g (7.7 mmol) of 5 (5-me thyl-2-picolylmercapto)-1H- theino/3,4-d/ imidazole were dissolved in 25 ml of DMF and 1.2 ml of triethylamine and 1.85 g (8.5 mmol) of di-tert.- butyl dicarbonate were added. After 2 hours a further 3 8 of the dicarbonate were added, and the mixture was stirred at 70°C for 4 hours. After DMF had been substantially evaporated off, the residue was ta- ken up in CH CL, and the solution was ghaken with wa- ter, dried over MgSO, and concentrated. The residue could be crystallized from diisopropyl ether or petro- jeum ether.
Melting point 115-117°Ce
Example 2H: tert. Butoxyoarbonyl-2-(3-nethyl-2-pioolylaul fins)” 1H-thieno/3,t-d/imidazole 1.1 g (3 mmol) of the title compound from Example 23 were dissolved in 50 ml of CH,CL,, and 50 ml of the
KH, PO, /Na, HPO), buffer solution from Example 22 were added. At 10°C a total of 900 mg (4.5 mmol) of m- chloroperbenzoic acid in CH,CL, was added dropwise in portions until the presursor has been completely used
Upe
The organic phase separated off, washed with water, dried © and consentrated.
The residue was first chromatographed on silica gel using : 10 ethyl acetate. The appropriate fractions were crystallis— ed from diethyl ether/petroleum ether, and the title com- pound was obtained.
Melting point 98°C (decomposition) ’ Example 25%
L-tert.-Butoxycarbonyl-2-5-methyl-2-picolylsulfinyl)-1H- thieno/3,l4-d/imidazole
The title compound was obtained by further elution with methanol/ethyl acetate (1:20) in the purification by column chromatography in Example 2h, + Melting point 127°C (decomposition)
Example 26:
L-test.-butoxycarboryl-2-(4-me thoxy-2-picolylmercapto)- 1H-thieno/3,4-d/imidazole 1.1 g (4.0 mmol) of 5_(l4-me thoxy-2-picolylmercapto)-1H~ thieno/3,4-d/ imidazole were dissolved in 15 ml of an-
) hydrous DMF, and 0.6 ml of triethylamine and 0.96 g (about 4.5 mmol) of di-tert.- butyl dicarbonate were added. After stirring at room temperature for 2 hours a further 0.32 g (1.5 mmol) of di-tert.-butyl 5S dicarbonate was added.
The precipitated product was filtered off with suction; water was added to the solution, which was extracted with CH, CL,» and the organic phase was dried over MgSO, and concentrated in vacuo. The oily residue crystalliz- ed from diethyl ether.
Melting point 152°¢C (decomposition)
Example 27: - (p-Ni trophenyloxycarbonyl) -2=(5-methyl-2-pieoly ners capto)-1H-thieno/3,4-d/ inidazole
The title compound was prepared in analogy to Example 17 from 5 (5-me thyl-2-picolylmercapto) -1H= thieno/3, k= d/imidazole and p-nitrophenyl chloroformate. After working up and chromatography on gilica gel using to- juene/ethyl acetate (1:1), the appropriate fractions were crystallized from ethyl acetate, and the title compound was obtainede
Melting point 165 ~168°C
Example 28: sy droxyme thyl-2- (home thoxy-2-picolylnercepto) =Hi- thieno/3,l4-d/imidazole
Under a nitrogen atmosphere, 0.7 ml of 37% steength aqueous formaldehyde solution in 3 ml of acetoni- trile was added dropwise to 1.6 g (5.8 mmol) of 2- (l—me thoxy-2-picolylmercapto) -1H-thieno/3, 4-d7imida~ zole dissolved in 50 ml of acetonitrile. The mixture wae then stirred at 70°¢ for 15 minutes, The solu- tion was concentrated in vacuo, washed with water and . saturated aqueous NaCl solution and dried over MgSO,»
The residue obtained after evaporation resulted after treatment with diisopropyl ether, in a semi~-crystal- line crude product with crystallized from ethyl ace~ : tate.
Melting point 125-127°C : Example 29:
L-Acetoxyme thyl-2-(4-me thoxy-2-picolylmercapto)-1H- thieno/3,4-d/imidazole 1.3g (4.2 mmol) of the title compound from Example 28 were dissolved in 25 ml of anhydrous pyridine, and 50 mg of 4-dimethylaminopyridine were added. Under a ni- trogen atomosphere and while stirring, 6.3 ml of ace- tic anhydride were added dropwise, and the mixtunes was stirred at room temperature for ome hour. It was then poured onto ice water, extracted with methylene chloride, and the organic phase was dried over Mgso,, and concentrated in vacuof{ The crystalline solid was recrystallized from ethanol.
Melting point 111- 113°C
Example 30:
STIEREE tnieno/3,-d/ imidazole
The title compound was prepared jn analogy to Example 28 from a ampiesisnerespie) ere d/imidazole
Example 31:
EES tnieno/3,i-d/ imidazole
The title compound was obtained in analogy to Example 29 from the title compound of Example 30, The result- : jng crude product was purified by chromatography on si- 1ica gel (ethyl acetate/toluens =211) and spontaneously } 15 crystallized from diisopropyl ether on geratchinge
Colorles® crystals, melting point g7-89°C. } Example 328 1 Ace toxynethyl-2-(571e PY _a-picolylsul finy1) =H ¢nieno/3,-d/ imidazole 0.67 g (2 mmol) of the title compound fro® Example 31 was dissolved in 30 ml of anhydrous CH, CL, and, under a nitrogen atmospheres 0.6 ml (2 mmol) of titanium tetra= _ 129 ~- \
isopropylate is added. Then at 0°C 0.6 ml (2 mmol) of a 3 M solution of tert.-butyl hydroperoxide in toluene was added dropwise. After 30 minutes the mixture was allowed to reach room temperature and wag then stirred for 20 hours, water was added, the precipitated white solid was filtered off, the orga- : nic phase was dried over MgSO0y,s the solvent was re- moved by distillation in vacuo, and the crude product was chromatographed on silica gel using toluene/ethyl acetate (1:5). Colorless crystals of the title com-. pound (Rg = 0.18) were obtained from diisopropyl ether.
Melting point 104 - 106°C.
Example 33: )-Hydroxyme thyl-2-(4-piperidino-2-chlore-2-picolylmer- capto) -1H-thieno/3,4-d/imidazole
The title compound was obtained in analogy to Example 28 from 5-(b-piperidino-3-chloro-2-picolylmercapto)-1t- thieno/3,4-d/imidazole
Melting point 132 - 134°C.
Example 3h: 1-Ace toxyme thyl-2-(4-piperidino-3-chloro-2-picolylmer= capto) =1H-thieno/3,k4-d/ imidazole
The title compound was obtained in analogy to Example 28 from the title compound of Example 33. The crude pro- duct was chrcmatographed on silica gel using toluene/
ethyl acetate (1:1).
Melting point 169 - 170°C gxample 35:
L- (i-Me thoxybenzyl) -2-(5-methyl-2-picolylmercapto) -1H- thieno/3,u4-d/imidazole
The sodium salt was prepared in analogy to Example 15 from 2.6 g (10 mmol) of 2-(5-methyl-2-picolylmercapto) -1H-thieno/3,4-d/imidazole, and was alkylated with 1.7 g (11 mmol) of 4-me thoxybenzyl chloride. After working up, the product was chromatographed on silica gel using
CH ,0L,,/methanol (50:1). The appropriate fractions were recrystallized from diethyl ether, and the title com- pound was obtained.
Melting point 114 - 116°C.
Example 36% (Ho thoxybenzyl) -2-(5-me thyl-2-picolyleul fonyd) -1t- theino/3,4-d/imidazole
The title compound from Example 35 was oxidized with 2 equivalents of m-chloroperbenzoic acid in CH,CL, and 20° Na HPO, /KH PO, puffer (as described in Example 22). The crude product was purified by chromatography (silica gel, toluene/ethyl acetate 1:4). The title compound crystal- lized from a little diisopropyl ether.
Melting point 148 -150°C.
Example 37: l-Acetyl-2-(5-methyl-2-picolylmercapto)~1H-thieno [3.4-d/imidazele
The title compound was obtained in analogy to Exam- ple 29 by reaction of 2-(5-methyl-2-picolylmercapto) ~-1H-thieno/3,4-d/imidazole with pyridine/acetic an- hydride/dimethylaminopyridine. After working up, the : crude product was dissolved in a little CH,CL, and chro- matographed on silica gel using toluene/ethyl acetate (1:1). The title compound crystallized from the appro- priate fractions. ’
Melting point 139 - 141°,
Example 38: 1-(1-Acetoxyethoxycarbonyl)=-2-(5-methyl-2-picolylmer~ . capto)-1H-theino/3,4-d/imidazole
In analogy to Example 15 the sodium salt was prepared from 2.6 g (10 mmol) of 2-(5-methyl-2-picolylmercapto) 1H-thieno/3,k-d/imidazole. At -10°C a solution of 2.7 g (10 Mmol) of 1 acetoxyethyl p-nitrophenyl carbonate in DMF was added dropwise. The reaction mixture was warmed to room temperature andj,after 2 hours, concen- trated in vacuo, water was added to the residue, and the mixtures was extracted with CH,CL, which dried over
MgSO, and concentrated,
The residue was chromatographed on silica gel using toluene/ethyl acetate (3:1). The title compound crystallized from the appropriate fractions.
Melting point 111-113°C.
In addition, a small amount of the title compound of Example 36 was obtained.
The compounds in Table 2 which follows were prepared in analogous manner.
Table 2
Exe A T rR’ rR" R’ r® rR’ g® RJ MePe ample ‘
No.
Ce : t 39. ss HHHH O-CH H H x 2HCl 177°¢ (decomp.) ~NEN 2 cH — 6 5 40. 8 sHEHEH -O-cH, HH 186°C (decomp.) —_ 2 ' = . . o ki. S SHHHH OCH H H H x 2HC1 206°C : NZ 25
Table (continuation) fe AT RE RY RS RS RT REO o.p. ample
No. 42. A S H H H H CH, H H x 2HC1 204°C pr 43. " S H H H H H CHy H x 2HBr 218°C 44 " SS H H H H H CH, H 136°C 45. " S H H H CH, H CH, H x 2HC 207°C (decomp.) 46. " SO H H H CH, H CH, H 156°C (decomp.) 47. " S H H H CHy OCH3 CH4 H 108-112°C 48. " S H H H CH3 OCH4 H H 174-177°C 49, " SO H H H CH; OCH; CH; H 190°C (decomp.) 50. " SO H H H CH, OCH H H 145°C {decomp .) . 51. " S H H H H H H H 126-129°C 52. SOH H H H H H H 148-149°C 53. " SOH H H H OCHHg H H 135°C (decomp.) 54. " S H H H CHyH H H > 320°C (decomp.) 85." SOH H H CHyH HH abovel55°C (decomp.) . " H _ ° 56. Re SOH H H H H C 3 H 120-123°C 55 57. : ] S$ H H HH H H H H x 2HC1 330°C
HC
58. u SOH H H H H H H 155-157°C 59. " S$ H H H H OCH; H H 217-222°C 60. " soH H H H OCH; H H 170-174°C - 13h = hi [i
Table (continuation)
Ex- AT RY ’* RS RE WJ rE RI np. ample '
No. 61. {I SOW H H H OCHy H H 142°C
CH,0,C ’ 62. s S H H H H CO) HH x 2HC1)320°C )
HC
0 63. 2 S H H H HH CH Hx 2H 250°C
Hy i 64. 7 S H H H H H CHy H 164°C (decomp.) 135 : : hd 65. $7 S HH -CHy-CHy- H HoH 147°C 66. " SOH H -CHyCHp- H HoH 93°C (decomp.) 2 67. S H H H H H C,Hg H x 2HC) 183°C (decomp. 68. " SOH H HH H H C Hg H >g5°C (decomp.) : 69. SH H HH -0CH H Hx 2HC) 181°C (decomp.)
CeHg 70. SOK H HH -0-CHy HH 178°C (decomp.)
Gets 71. SH OH HH -0-(CH pH Hx 2HC1 170°C (decomp.) 0- CH 722 CS HOH HH -D-(CHp HH 114°C 0- CH : n - - ° “0 73 SOH H HH -0-(CH)p H H 105°C
OCH; 74 S H H H H H H CH xZHC1>300°C 75 SOH H H H H H CHy 125°C 76 S H H H “) H H x 2HCI 194°C (decomp.) : 77 SH H H CI" H H >90°C 78 S H H H C1 OCH HH x 2HC1>250°C 9 S H H H C1 OCH, HH 156°C go SOH H H OO OCH, H H abovel60°C (decomp.)
Co - 135 - H
CL
Table (continuation) ’ ee AT RI RRS RS RT RP RY n.p- ample
No- )
H,COC ce JR sw WH HH 117°C
Hy, ° 82 Cl S$ H H HH H H H H 102°C
CON(CoHs) : 1 83 S_ S H H H H OCH; HW Hx2HC1 168°C 1 > “00CH;
H3 84 ST S$ H H H H OCH, HH x 2HC)abovel88°C -
Example 85: 2-/8-(2,2,3,3,4,4,4-heptafluorobutyloxy) -2-picolyl-" sulfinyl/-1H-thieno/3,4~d/ imidazole ) a) 4-Nitro-2-picoline N-oxide
While cooling with ice, 163.5 g (1.5 mol) of 2-picoline
N-oxide were introduced to 250 ml of 98 ¢ sulfuric acid.
At room temperature, 250 ml of 100 % nitric acid were added dropwise, and subsequently, the reaction mixture was carefully warmed up to 80°C, with stirring, and was stirred for 3 hours at this temperature. 35 . -7 136 ~ ~ /!
Ph
Po
Co {od
The reaction mixture was allowed to cool down to room temperature was pored in 1 1 of ice and neu- tralized with concentrated sodium hydroxide solu~ tion, with cooling and stirring. A yellow slush of crystals precipitated, which was filtered with suction, washed with a small portion of ice water and was dried. yield: 186 g (80 % of the theory), mpe: 156°C b) 4-(2,2,3, 3,1, b-heptaf luorobutyloxy)-2=pieoline
H-oxide 15.4 g (0.1 mol) of the compound of Example 85.a) were dissolved in 150 ml of dimethylformamide, h1.4 g (0.3 mol) of pulverized anhydrous potassium carbonate and 2% g (0.11 mol) of 96 % 2,243,353, ky, h-heptafluorobus 1% tanol were added, and the reaction mixture was warmed to 70°C, with stirring. After I hours, additional 13.9 g of potassium carbonate were added, and the mixture was stirred for further 6 hours. The mixture was allowed to cool down to room temperature, the salts were fil- tered off, and were washed with a small portion of di- methylformamide.
The filtrate was concentrated in vacuo, and the residue was extracted with water.ethylacetate. The organic la- yer was dried with Na 50s concentrated, and filtered over silica gel with ethyl acetate/ methanol 3:1. After
. concentrating the filtrate, 22.7 g (74 % of the theory) of the title compound, mp.: 65°C, were isolated. c) 2-Chloromethyl-4-(2,2,3,3,3,4,4,4) -heptafluore- butyloxy pyridine 49,1 g of the compound of Example 85.b) in 450 ml of acetic anhydride were stirred at 90°¢c for 1 hour.
A control with TLC showed the complete conversion in- to 2-acetyloxymethyl “4o(2,2,3,3,4,4,4)-heptafluoro- butyloxypyridine
The solvent was evaporated off in vacuo, the oily re- sidue was dissolved in 500 ml of methanol, and a solu- tion of 12 g of sodium hydroxide in 50 ml of water was added. After stirring at room temperature for 2 hours., T1C control showed the complete saponification of the acetate.
The solvent was removed in vacuo, the residue was dis- solved in methylene chloride and washed with water.
After drying with Na 80) the organic layer was concen- C trated in vacuo. The residue was dissolved in 500 ml of chloroform and 50 ml of thionyl chloride were added dropwise, with stirring. The reaction mixture was heat- ed to reflux for 1 hour, and then allowed to cool down.
The solvent was removed in vacuo, the residue was dis- solved in methylene chloride, the solvent was again evaporated off, the residue was taken up in diiso- propyl ether, and the title compound crystallized. yield: 39 g (67 % of the theory)s mp. 98-101°C d) -[R-(2,2,3, 3,11 hohe ptaivorobutyloxy) 2opheotss mercapto]/-1i-theino/3,4-d/inidazole 18.7 g of theino/3,4-d7imidazole-2-thiol were added to a sodium methylate solution (prepared from 8.2 g of so- dium and 300 ml methanol), and, during stirring, & solu- tion of 43.8 g of the compound of Example 85. ¢) in 100 ml of methanol was added.
After heating to reflux for 1 hour, a TLC control showed that the reaction was complete ‘ ed.
The solvent was evaporated off in vacuo, the residue was dissolved in methylene chloride , and washed with wa- ter.
The organic layer was dried with Na, S80, and concen- trated in vacuo.
The residue was triturated with diiso- propyl ether, filtered suction and dried. . : Yield: 43 8 (80 % of the theory) ymp.: 117°C. e) io(242,3, 32k beheptatiuorobutylosy) -2ophectiis sul finyl/-1H-thieno/3,4-d/inidazole 40.0 g of the mercapto compound of Example 85.d) were dissolved in 800 ml of methylene chloride, and 500 wl of an agueous phosphate puffer (pH-7) were added.
The suspension was gtirred vigorously, and a solution of 20 - g of 77 % me ta-chloroperbenzoic acid in 150 ml methylene chloride were added dropwise at 0o°c.
The reaction mix-
ture was stirred at this temperature for additional 10 minutes, and, after starch-iodine paper no longer showed the presence .of the peracid, the organic la- yer was separated from the aqueous layer. The aqueous layer was extracted with 100 ml of methylene chloride, the organic layers were combined, dried with Ng,80, and concentrated in vacuo until the volume was approxiw- mately 100 ml. #fter addition of 800 ml of diisopropyl ether, the crystallization (which had already been start- ed) waa completed. The crystals were filtered off with suction and were dried.
Yield: 32 g (76 % of the theory); mp.: 140°C (decomp.)
The following compounds were prepared in analogous man~ ner.
Example 86: ' 2-/1(2,2,3,3,4,4,5,5~-0octafluoropentyloxy)-2~picolylsul-~ finyl/-1H-theino/3,4-d/imidazole : Example 87: 2-/-(2,2,3,3,4,4,4-heptafluorobutyloxy)~2-picolylsul=- 26 finyl/-4,6-dimethyl-1H~-thieno/3,4-d/imidazole mp.: 147°C (decomp.)
Example 88: 2-/B-(2,2,2-trifluoroethyloxy)-2-picolylsulfinyl/-4,6~ dimethyl-1H~-thieno/3,4-d/imidazole mp.§ 163-165°C (decomp.)
Example 89: 2. [T=(2,2,3,3- te trafluoropropyloxy) ~2-picolylents sulfinyl/-l,6- dimethyl-1H-theino/3,4-d/inidazole mp: 144-147°C (decomp.)
Example 90: : 2. /T-(2,2,3,3,3-pentafluoropropyloxy) ~2-picolyleuis finy17h,6-dinethyl-1i-thieno/3, 4-d/ imidazole mp.: 147 -151°¢ (decomp.)
Example 91: 2- [3-ne thyl-A=(2,2,2-trifluoros thyloxy) -2-picolyleri- oo finyl/~1H~thieno/3,4-d/ imidazole mp.: 121°C (decomp.) : Example 92: 2-/5-nethy1-i-(2,2,2- trifluorosthyloxy) ~2-picolyienis : finyl/-1H-thieno/3,4-g/ imidazole
MePe 163°C (decomp.)
Example 93: . -[5-NothyL(2,2,3 3 3-pentativoropropyloxy) -2-pieelyis sulfinyl/-1H-theino/3,k-d/inidazole mp. 145°C (decomp.)
Example gh: [3a thyL-h=(2,2,3,34lty by bemoptatloorobutyloxy) =” fcolyleul finyl-1-theino/3, -ginidazole mp. 115% (decomp.) - 1b -
Example 95: 2-/B-(2,2,2-trifluoroe thyloxy)-2-picolylsulfinyl/-1H- thieno/3,4-d/imidazole . mp.s132-136°8 (decomp.)
Example 96: 2-/B-(2,2,3, 3-tetrafluoropropyloxy) -2-picolylaulfiny1/-1h- thieno/3,4-d/imidazole mp.t 152°C(decomp.)
Example 97: : 2-/F-(2,2,3,3, 3-pentafluoropropyloxy) -2-picolyleulfinyl/- 1H- thieno/3,4-d/imidazole mpes 148-152°C (decomp.)
Example 98: 2-/B=(1,1,1,3,3, 3-hexafluoroisopropyloxy)=2-picolyleul fi- nj17-1H-theino/3,4-d/inidazole a)h-(1,1,1,3,3,3-Hexafluoroisopropyloxy)-2-picoline N- oxide
The titie compound was obtained in analogy to Example i 85.b) using potassium tert. butylate as a base. b) 4-(1,1,1,3,3,3-Bexafluoroisopropyloxy)-2-picoline 4.5 g (16 mmol) of the compound of Example 98.) were dissolved in 100 ml of methanol and hydrogena- ted, using Raney nickel as a catalyst.
MS: m/e= 259 (M*, 100%), 240 (30 %), 220 (8 %) 80 (77 %) c) 3-Chloromethyl-l-(1,1,1,3,3,3-hexafluoroisopropy= - 1he -
loxy)-pyridine hydrochloride 2.2g (8.6 mmol) of the compound of Example 98.b) were dissolved in 50 ml tetrachloromethane, 0.56 g of dime thylformamide and 1.4 g (5.6 mmol of tri- 5 . chloroisocyanuric acid were added, and the react- jon mixture was heated to reflux for 1 hour. A pre- ’ cipitate was filtered off, 30 ml of 1N hydrochloric acid in methanol were added to the filtrate and the solvent was evaporated off in vacuo. The crude pro- duct was used without further purification for the following step. d) p-/E-(1,1,1,3,3,3-Hexaf Luoroiaopropyloxy)=Bopiser yimercapto/1f-thieno/3 ,4-d7imidazole
The title compound was obtained from the Example 98. b) and the thieno/3,4-d7imidazole-2-thiol in analogy to
Example 85 .d) e) J f-(3.4141, 343, 3-liesatluorotsopropyloxy)-2-pheo tis: sulfinyl7-18-thieno/3,4-d/inidazole
The title compound was obtained* from the compound of
Example 98. e); mp: 168-169°C [from diethyl ether/. * jin analogy to Example 85.€)

Claims (1)

  1. PATENT CLAIMS:
    1. A compound of the formula 1 . rR? R B ! TI. ' : S- T - © wl 2 (1) / : Rh] 1 1% R’ in which . 1 R r!
    ~ . . A ° represents §) B) ¢ or cj P 2 LY X 2 / \ ’ E 2 S R R ? denotes -8-, -SO- or -80,-, . rR and R® are identical or different and denote hydro- gen, halogen, cyano, nitro, (C,-Cg)-alkyl, (c,-Cg) -hydroxyalkyl, (C,-C¢) alkoxy, (Cy -Cq) -alkylmercaptos C = - - - - ( 1 Cg) alkylsulfinyl, (cy Cg) alkylsulfonyl, (c, Cg)-alkylcarbonyl, (C,-Cg)-alkoxycarbonyl, carba-~ moyl, N-(C,-C,)-alkylearbamoyl, N,N-di-(C,-Cy)~ alkylcarbamoyl, (C,~Cg)-alkylcarbenyloxy, (C5-Cg) -cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenyl- sulfonyl, phenylsulfinyl, sulfamoyl, N-(C;-Cy)~ alkylsulfamoyl or N,N-di-(C,-C,)-alkylsulfamoyl or, - 1b if A is as defined above under (a) or (c), can also together denote-/CH 7 - oF -CH=CH-CH=CH~-, one CH, group optionally being replaced by 0, Sy 80 or 80, Rr denotes hydrogen (c,-Cg)atkanoyls (C,-Cg)-alkyl- carbamoyl or another physiologically tolerated nie protective group which can be eliminated, in an acid medium and/or under physiological conditions, Rt and R are jdentical or different and dehote hydro- gen or (C=C) -alkyls 6 7 gB 9 R, Ry R and R’ are jdentical or different and de- note hydrogen, halogen, (Cy=C;p)-alkyls (C,=Cy 5)" alkoxy, =0/-Ch,7 Cel(ags1-g)T8" NRE" (c,- C2)" alkoxy-(C,=Cyp)-alkyls (0,-C, p)-alkoxy-(Cy- Cp) -alkoxy or (C=C, aralkyloxys or 5 6 RZ and R together represent ~[ CB, Tis 1 R and R are identical or different and denote hydro- : gen or (C,-C,)-alkyls or ' ! t ¢ -/Gi7,- in which one CH R and R together represent - on” n which one 2 group can be replaced by 0, S, N-(C,-C),)-alkanoyl- imino or N-(0,-C,,) -alkoxyc,rbonyLinines f is an integer from 1 to 10, - 1h5 = g js 1 to (2f + 1), h is 4, 5 or 6, i is 1, 2 or 3, x is 0 or 1, and mn is 3 or 4, and its physiologically tolerated salts. 2e A compound of the formula I as claimed in Claim 1, in which Rr’ denotes hydrogen or its physiolo- gically tolerated salts. .
    3. A compound of the formula 1 is as claimed in Claim 1, in which A is as defined under (b) in claim 1 or its physiologically tolerated salts. . L, A compound of the formula I as claimed in claim 1, in which T represents -50-, or its physiolo- gically tolerated salts. 5e A compound of the formula I as claimed in claim 1, in which rR and R® are identical or different and denote hydrogen, (C,-C5)-alkyl, halogen, Cy- C,)-alkoxy, or (¢,-C),)-alkoxycarbonyl, R js as defined in claim 1, : . L 5 R' and R” each denote hydrogen, : - 1h6 =
    8%, Rr’, g® and rR are identical or different and denote hydrogen, halogen, -0-/=cH, 7
    - C.- - - CH(2pe1-2) 8" ( 1 C4) alkyl, (cy Cy) -alkoxy, benzyloxy or (C,=C,)-alkoxy-(Cy= C,)-alkyls and f, g and x are as defined in claim 1, or its phy- siologically tolerated salts.
    6. A compound of the formula I as claimed in claim 1, in which Rr and R® are identical or diffefent and denote hy- drogen OY (Cy-C5)-alkyls Rr js an defined in claim 1, R and R’ each denote hydrogen, g? and RS are jdentical or different and denote hydrogen, chlorine, methyl or ethyl, r? denotes hydrogens 7 R denotes hydrogen, 0 [Ch, 7 CoH (2£41-)F yo (C=C) 8lkoxYs (c,-C,)-alkyl or benzyloXys and f, 8 and x are as fined in claim 1, OT its phy- siologically tolerated salts. 7 (2-picolyisulfinyl)-1H-thisno Syd inidssee or its physiologically tolerated salts;
    8. tome thoxy-z-prctylaut fam) -Hi-tntens5ikd] - 1b7
    - . ee . » 26 1 {0% imidazole or its physiologically tolerated salts;
    9. 5 (=e thoxy-3-me thyl-2-picolyl-sul finyl)-1i- thieno/3,4-d/imidazole, or its physiological- ly tolerated salts.
    10. 2 (home thoxy-3,5-dime thyl -2-picolylel finyl)-1i- thieno/3,4-d/imidazole, or its physiologically tolerated salts.
    11. > (3-me thyl-2-picolylaul tinyl)-18-thieno/3 md jmidazole, or its physiologically tolerated salts.
    12. 2-(5-methyl-2-picolylsul £iny1)-1H-thieno/3, 4-47 jmidazole, or its physiologically tolerated salts.
    13. 2-(4-methyl-2-picolylsul finyl)-1H- thieno/3, h-a7 imidazole, or its physiologically tolerated salts 1k, (5-0 thyl-2-picolylsuliny1) -1H-tnisno/3,b-d/ imidazole, or its physiologically tolerated salts
    15. 4, 6- dime thyl-2-(5-methyl-2-picolylsulfinyl)=3R= thieno-/3,4-d/ imidazole or its physiologically tolerated salts.
    16. 2-(3-chloro-4-me thoxy-2-picolylsul finyl)-1B- thieno/3,4-d/imidazole or its physiologically tolerated salts.
    17. A compound as claimed in claim 1, which is
    2. [B-(242,33, 4, b-heptatluorobutyloxy)=2- Jicolylsul finyl/-1H-thieno/3,-d/inidazole or its physiologically tolerated salts.
    18. A pharmaceutical formulation comprising a gastric - acid inhibitory an effective amount of a compound as claimed in claim 1 or of ite physiologically tolerated salt, and a physiologically acceptable vehicle.
    19. A method for the inhibition of gastric acid sec~ retion by administration of an effective amount of a compound as claimed in claim 1 or of its phy- siologically tolerated salt.
    20. A method of treating inflammatory intestinal diseases in 8 patient, comprising administering to said patient an effective amount of a compound , as claimed in claim 1 or its physiologically tole~- rated salt.
    21. A method of treating ofdiarrhea in a patient, com- prising administering to said patient an effective amount of a compound as claimed in claim 1 oT its physiologically tolerated salt. HANS-JOCHEN LANG ROBERT RIPPEL ANDREAS We. HERLING KLAUS WEIDMANN Inventors
PH36339A 1986-02-20 1988-01-11 Substituted pyridylmethyl mercapto sulfinyl-or-sulfonyl thienoimidazole derivatives pharmaceutical compositions containing them and their use as inhibitors of gastric acid secretion PH26407A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19863605395 DE3605395A1 (en) 1986-02-20 1986-02-20 Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical preparations containing them, and their use as gastric acid secretion inhibitors
DE19863623683 DE3623683A1 (en) 1986-07-12 1986-07-12 Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical preparations containing them and their use as gastric acid secretion inhibitors
DE19873700436 DE3700436A1 (en) 1987-01-09 1987-01-09 Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical preparations containing them and their use as inhibitors of gastric acid secretion
PH3487387 1987-02-18

Publications (1)

Publication Number Publication Date
PH26407A true PH26407A (en) 1992-07-02

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PH36339A PH26407A (en) 1986-02-20 1988-01-11 Substituted pyridylmethyl mercapto sulfinyl-or-sulfonyl thienoimidazole derivatives pharmaceutical compositions containing them and their use as inhibitors of gastric acid secretion

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Country Link
PH (1) PH26407A (en)

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