Hoffmann-La Roche Inc.

Fernand Schneider

Ulrich Widmer

Pierre Barbier

Ulf Fischer

Sven Taylor

Josef Stadlwieser

Isabelle Huber

Karl Bernauer

Karlheinz Pfoertner

Hans Schmid

Rene Zurflueh

Heinz Hasler

Widmer Ulrich

Hans Schmid, Deceased

By Maria Schmid-Suter, Heir

By Jeannette Wawrla-Schmid, Heir

By Ernst Schmid-Gautschi, Heir

By Mary Baumann-Schmid, Heir

The compounds of formula I: wherein R.sup.1 --R.sup.9, R.sup.15, A, X, Y, and Z have the meaning given in the specification are active as protein kinase inhibitors and can be used as medicaments, particularly for the treatment of inflammatory skin disorders and alopecia.

Azepanes and their ring homologues having protein kinase inhibiting

A compound of the formula ##STR1## useful for treating vitamin D dependent disorders.

Vitamin D derivative

The compounds of formula I ##STR1## wherein R.sup.1 -R.sup.9, R.sup.15, A, X, Y, Z and n have the meaning given in the specification are active as protein kinase inhibitors and can be used as medicaments, particularly for the treatment of inflammatory skin disorders and alopecia.

The compounds are of the class of bi- and tricyclic pyridone derivatives of the formula ##STR1## wherein various substituents are as described in the specification, useful in the control of prevention of muscle tensions, stress conditions, insomnia, anxiety states and/or convulsions.

Tricyclic pyridine derivatives

Racemic compounds of the formula ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n are as described herein, enantiomers and diastereomers thereof, and salts of these esters with weak acids, are described. These compounds inhibit pancreas lipase and are useful agents in the treatment of obesity, hyperlipaemia, atherosclerosis and arteriosclerosis.

Oxetanones

Compounds of the formula ##STR1## wherein R.sup.1 and R.sup.2 independently C.sub.1-17 -alkyl which is saturated or optionally interrupted by up to 8 double or triple bonds and/or optionally interrupted by an O or S atom, which is present in other than the .alpha.-position to an unsaturated C atom; or phenyl, benzyl or --C.sub.6 H.sub.4 --X--C.sub.6 H.sub.5 ring-substituted by 0 to 3 C.sub.1-6 -alkyl-(O or S).sub.1 or 0 groups, and X is oxygen, sulfur or (CH.sub.2).sub.0-3, with the proviso that when R.sup.1 is n-hexyl and R.sup.2 is undecyl or 2Z,5Z-undecadienyl, at least one of the asymmetric C-atoms present in the oxetanone ring and in the .beta.-position to the latter has the R-configuration, an enantiomer or a diastereomer thereof are described. These compounds inhibit pancreas lipase and are useful agents in the treatment of obesity, hyperlipemia, atherosclerosis and arteriosclerosis.

The compounds of the formula ##STR1## wherein R.sub.a, R.sub.b, R.sub.c, R.sub.d are defined in the specification and pharmaceutically acceptable addition salts are disclosed. The compounds of formula I have valuable pharmacological properties and can be used for the control of prevention of illnesses. In particular, they have muscle relaxant, seditive-hypnotic, anxiolytic and/or anticonvulsive activity and can accordingly be used in the control or prevention of muscle tensions, stress conditions, isomnia, anxiety states and/or convulsions.

Tricyclic pyridone derivatives

The compounds are of the class of bi- and tricyclic pyridone derivatives of the formula ##STR1## wherein the various substituent are as described in the specification, useful in the control of prevention of muscle tensions stress conditions, insomnia, anxiety states and/or convulsions.

The invention is directed to a process for the manufacture of pancreatic lipase-inhibiting oxetanone ethyl esters of the formula ##STR1## wherein X is undecyl or 2Z,5Z-undecadienyl; C.sub.6 is n-hexyl; Y is isobutyl and Z is formyl or Y is carbamoylmethyl and Z is acetyl; which process comprises esterifying the corresponding oxetanone ethanols, or hydrogenating the 3-undecenyl group in corresponding oxetanone ethyl ester starting materials to the undecyl group X, or N-formylating or N-acetylating corresponding primary amines.

Oxetanones and process for their production

Compounds of the formula ##STR1## wherein Q.sup.1 and the nitrogen atom taken together are a group of the formula &gt;N--CH.sub.2 CH.sub.2 -- (a), &gt;N--CH.sub.2 CH.sub.2 CH.sub.2 -- (b), &gt;N--CH.dbd.CH-- (c), &gt;N--CH.sub.2 --CH.dbd.CH-- (d), &gt;N--CH.sub.2 --S(O).sub.p -- (e), &gt;N--CH.sub.2 CH.sub.2 --S(O).sub.p -- (f) or &gt;N--CH.dbd.CH--S(O).sub.p -- (g), p is the integer 0, 1 or 2, Ra is a phenyl, pyridyl or thienyl group which is optionally substituted by halogen, trifluoromethyl, nitro, lower alkyl or lower alkoxy, Rb and Rc each, independently, are hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or nitro and the dotted line signifies an optional bond, or Rb and Rc together with the carbon atom denoted by .alpha. are a group of the formula &gt;C.alpha.--S--CH.dbd.CH-- (h), &gt;C.alpha.--CH.dbd.CH--S-- (i) or &gt;C.alpha.--CH.dbd.CH--CH.dbd.CH-- (j) which is optionally substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino or mono- or di(lower alkyl)amino, and the dotted line signifies an additional bond, Rd is the group of the formula --(A.sup.1).sub.m --(CO).sub.n --(Q.sup.2 A.sup.2).sub.q --R.sup.1, m, m and q each, independently, are the integer 0 or 1, A.sup.1 is lower alkylene, A.sup.2 is lower alkylene, a direct bond or the group --CO--, Q.sup.2 is an oxygen atom or the group --NR.sup.2 --, R.sup.1 is hydrogen, hydroxy, cyano, nitro, halogen, lower alkoxy, lower alkyl, lower alkoxycarbonyl, aryl, a group of the formula --NR.sup.3 R.sup.4 or a 5-membered, saturated, partially unsaturated or aromatic heterocycle which is attached via a carbon atom and which is optionally substituted by one or two lower alkyl groups and optionally substituted by a (C.sub.3-6)-cycloalkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl, oxo or alkylenedioxy group, R.sup.2 is hydrogen, lower alkyl or aryl, R.sup.3 and R.sup.4 each, independently, are hydrogen, lower alkyl, lower alkoxyalkyl, lower dialkoxyalkyl, lower alkylenedioxyalkyl, lower cyanoalkyl, lower haloalkyl, lower hydroxyalkyl, lower dihydroxyalkyl, lower alkanoyl, lower alkoxycarbonyl or a (C.sub.3-7)-cycloalkyl group which is optionally substituted by hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, oxo, carbamoyl, mono- or di(lower alkyl)carbamoyl or by lower alkylenedioxy or together with the nitrogen atom is a 3- to 7-membered, saturated N-heterocycle which is optionally substituted by one or two lower alkyl groups and optionally substituted by one or two hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl, oxo or lower alkylenedioxy groups and which can contain as a ring member an oxygen or sulfur atom or the group &gt;N--R.sup.5, and R.sup.5 is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkanoyl, lower alkoxycarbonyl, carbamoyl or mono- or di(lower alkyl) carbamoyl, with the proviso that n is 0 when q is 1 and A.sup.2 is the group --CO--, that R.sup.1 is other than cyano, nitro, halogen or lower alkoxycarbonyl when q is 0 and n is 1 or when q is 1 and A.sup.2 is --CO--, and that R.sup.1 is other than hydroxy, cyano, nitro, halogen, lower alkoxycarbonyl, lower alkoxy and --NR.sup.3 R.sup.4 when q is 1 and A.sup.2 is a direct bond, or a pharmaceutically acceptable acid addition salt of a compound of formula I which has one or more basic substituents, are described. The compounds of formula I possess pronounced muscle relaxant, sedative-hypnotic, anticonvulsive and anxiolytic properties and have low toxicity.

The compounds of the formula ##STR1## wherein Ra,R.sub.b,R.sub.c R.sub.d are defined in the specification and pharmaceutically acceptable addition salts are disclosed. The compounds of formula I have valuable pharmacological properties and can be used for the control or prevention of illnesses. In particular, they have muscle relevant, seditive-hypnotic, anxiolytic and/or anticonvulsive activity and can accordingly be used in the control or prevention of muscle tensions, stress conditions, isomnia, anxiety states and/or convulsions.

Compounds of the formula ##STR1## or a pharmaceutically acceptable acid addition salt of a compound of formula I which has one or more basic substituents, are described. The compounds of formula I possess pronounced muscle relaxant, sedative-hypnotic, anticonvulsive and anxiolytic properties and have low toxicity.

Tricyclic pyridine derivatives and pharmaceutical compositions

The invention relates to with novel thiazolidine derivatives of the formula ##STR1## wherein X is methylene, oxygen or sulfur; R.sup.1 is halogen; R.sup.2 is hydrogen, nitro, cyano, OR.sup.3 or NHR.sup.3 ; or R.sup.1 and R.sup.2 both simultaneously are hydrogen or nitro; R.sup.3 is hydrogen, alkyl, acyl, --CO--OR.sup.4 or --CO--NHR.sup.4 ; and R.sup.4 is alkyl, unsubstituted or substituted aryl or aralkyl, and their salts with physiologically compatible cations. The compounds of formula I are useful in the treatment of metabolic disorders.

Growing community of inventors

Basel, Switzerland

Fernand Schneider