ZA200107833B - Glucokinase activators. - Google Patents

Glucokinase activators. Download PDF

Info

Publication number
ZA200107833B
ZA200107833B ZA200107833A ZA200107833A ZA200107833B ZA 200107833 B ZA200107833 B ZA 200107833B ZA 200107833 A ZA200107833 A ZA 200107833A ZA 200107833 A ZA200107833 A ZA 200107833A ZA 200107833 B ZA200107833 B ZA 200107833B
Authority
ZA
South Africa
Prior art keywords
cyclopentyl
phenyl
propionamide
thiazol
urea
Prior art date
Application number
ZA200107833A
Inventor
Fred Thomas Bizzarro
Antonino Focella
Nancy-Ellen Haynes
Robert Francis Kester
Ramakanth Sarabu
Wendy Lea Corbett
Joseph Francis Grippo
George William Hollard
Paige E Mahaney
Original Assignee
Hoffmann La Roche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of ZA200107833B publication Critical patent/ZA200107833B/en

Links

Description

7 WO 00/58293 PCT/EP00/02450
Glucokinase activators
Glucokinase (GK) is one of four hexokinases that are found in mammals [Colowick, S.P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, NY, ~~ pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic -cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S.R.,
Kelly, K.L., and Ruderman, N.B. in Joslin's Diabetes (C.R. Khan and G.C. Wier, eds.),
Lea and Febiger, Philadelphia, PA, pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations (<1 mM).
Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (=10-15 mM) levels following a carbohydrate-containing meal [Printz, R.G., Magnuson, M.A., and Granner,
D.K.in Ann. Rev. Nutrition Vol. 13 (R.E. Olson, D.M. Bier, and D.B. McCormick, eds.),
Annual Review, Inc., Palo Alto, CA, pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in f-cells and hepatocytes (Meglasson, M.D. and Matschinsky, F.M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferme, T., Riu, E., Bosch, F. et al., FASEB 7. 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in B-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of } glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser,
B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type
IT diabetes. Glucokinase activators will increase the flux of glucose metabolism in B-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
This invention provides a compound, comprising an amide of the formula I:
Re
H
A _N—R*
G I
0
Rr? 1
R I wherein
R' and R? are independently hydrogen, halo, amino, hydroxyamino, nitro, cyano, sulfonamido, lower alkyl,-OR’, -C(O)OR?®, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl or lower alkyl! sulfinyl;
R’ is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms;
© WO 00/58293 PCT/EP00/02450
R* is -C(O)NHR¥; or an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being : 5 nitrogen which is adjacent to the connecting nng carbon atom; said mono- substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, -(CH,),-OR?, -(CH)s-C(O)OR’, -(CH,),-C(O)NHR?, -C(0)-C(O)OR", -(CHy),-NHR?;
R* is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl, -(CH;)n-C(O)OR® or -C(0)-(CH,),-C(O)OR’;
R’ is hydrogen, lower alkyl or perfluoro-lower alkyl;
Co R®, R’ and R® are independently hydrogen or lower alkyl; and nis0,1,2,3o0r4,; » 15 or a pharmaceutically acceptable salt thereof.
In the compound of formula I, the * indicates the asymmetric carbon atom in this compound. The compound of formula I may be present either as a racemate or in the “R” configuration at the asymmetric carbon shown. The “R” enantiomers are preferred.
The compounds of formula I have been found to activate glucokinase in vitro.
Glucokinase activators are useful for increasing insulin secretion in the treatment of type
II diabetes.
The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier and/or adjuvant.
Furthermore the present invention relates to the use of such compounds for the
- vv ” preparation of medicaments for the treatment of type II diabetes. The present invention also relates to processes for the preparation of the compounds of formula I. In addition, the present invention relates to a method for the therapeutic treatment of type II diabetes, which method comprises administering a compound of formula I to a human being or an animal.
As used throughout this application, the term “halogen” and the term “halo”, unless otherwise stated, designate all four halogens, i.e. fluorine, chlorine, bromine and iodine. A preferred halogen is chlorine.
As used herein, the term “lower alkyl” includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl. With regard to R’, isopropyl and n-propyl are preferred. “Halo lower alkyl” as used herein designates a lower alkyl group wherein one of the hydrogens is replaced by a halogen as defined above, which replacement can be at : any site on the lower alkyl, including the end. 'A preferred halo lower alkyl group is chloroethyl. Similarly, “hydroxy lower alkyl” designates a lower alkyl group where one of the hydrogens is replaced by a hydroxy, at any site including the end. Preferred hydroxy
Jower alkyl groups include ethanol, isopropanol, and n-propanol. As used herein, “perfluoro-lower alkyl” means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro. Among the preferred perfluoro- lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc.
ST " As used herein, “lower alkyl thio” means a lower alkyl group as defined above Co where a thio group is bound to the rest of the molecule. Similarly “perfluoro-lower alkyl thio” means a perfluoro-lower alkyl group as defined above where a thio group is bound to the rest of the molecule.
As used herein, “lower alkyl sulfonyl” means a lower alkyl group as defined above where a sulfonyl group is bound to the rest of the molecule. Similarly “perfluoro-lower alkyl sulfonyl” means a perfluoro-lower alkyl group as defined above where a sulfonyl group is bound to the rest of the molecule.
TWO 0058293 PCT/EP00/02450
As used herein, “lower alkyl sulfinyl” means a lower alkyl group as defined above where a sulfinyl group is bound to the rest of the molecule.
As used herein, “hydroxyamino” designates an amino group where one of the hydrogens is replaced by a hydroxy.
As used herein, “cycloalkyl” means a saturated hydrocarbon ring having from 3 to — 10 carbon atoms; preferably-from-3-to—7-carbon atoms; such-as cyclopropyl; cyclobutyl;~-- cyclopentyl, cyclohexyl, cycloheptyl, etc. A preferred cycloalkyl is cyclopentyl.
As used herein, the term “lower alkenyl” denotes an alkylene group having from 2 ) to 6 carbon atoms with a double bond located between any two adjacent carbons of the group. Preferred lower alkenyl groups are allyl and crotyl.
As used herein, the term “lower alkoxy” includes both straight chain and branched chain alkoxy groups having from 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy,
So isopropoxy, preferably methoxy and ethoxy. to As used herein, the term “aryl” signifies aryl mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc. which can be unsubstituted or substituted in one or more to positions with halogen, nitro, lower alkyl, or lower alkoxy substituents and polynuclear
Co aryl groups, such as naphthyl, anthryl, and phenanthryl, which can be unsubstituted or substituted with one or more of the aforementioned groups. Preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly phenyl. The term “arylalkyl” denotes an alkyl group, preferably lower alkyl, in which one of the hydrogen atoms 1s replaced by an aryl group. Examples of arylalkyl groups are benzyl, 2- phenylethyl, 3-phenylpropyl, 4-chlorobenzyl, 4-methoxybenzyland the like.
As used herein, the term “lower alkanoic acid” denotes lower alkanoic acids containing from 2 to 7 carbon atoms such as propionic acid, acetic acid and the like. The term “lower alkanoyl” denotes monovalent alkanoyl groups having from 2 to 7 carbon atoms such as propionoyl, acetyl and the like. The term “aroic acids” denotes aryl alkanoic acids where aryl is as defined above and alkanoic contains from 1 to 6 carbon atoms. The term “aroyl” denotes aroic acids wherein aryl is as defined hereinbefore, with pe WO 00/58293 PCT/EP00/02450 the hydrogen group of the COOH moiety removed. Among the preferred aroyl groups is benzoyl. :
The heteroaromatic ring in R* can be an unsubstituted or mono-substituted five- or - = six-membered heteroaromatic ring having from 1 to 3 heteroatoms selected from the oo group consisting of oxygen, nitrogen or sulfur and connected by a ring carbon to the amine of the amide group shown. The heteroaromatic ring contains a first nitrogen heteroatom adjacent to the connecting ring carbon atom and if present, the other heteroatoms can be sulfur, oxygen or nitrogen. Such heteroaromatic rings include, for example, pyrazinyl, pyndazinyl, isoxazolyl, isothiazolyl, and pyrazolyl. Among the [0 preferred heteroaromatic rings are included pyridinyl, pyrimidinyl, thiazolyl, oxazolyl and imidazolyl. These heteroaromatic rings which constitute R* are connected via a ring carbon atom to the amide group to form the amides of formula I. The ring carbon atom of : the heteroaromatic ring which is connected via the amide linkage to form the compound of formula I cannot contain any substituent. When R* is an unsubstituted or mono- substituted five-membered heteroaromatic ring, the preferred rings are those which contain a nitrogen heteroatom adjacent to the connecting ring carbon and a second heteroatom adjacent to the connecting ring carbon or adjacent to said first heteroatom.
The preferred five-membered heteroaromatic rings contain 2 or 3 heteroatom with thiazolyl, imidazolyl, oxazolyl and thiadiazolyl being especially preferred. When the heteroaromatic ring is a six-membered heteroaromatic, the ring is connected by a ring carbon to the amine group shown, with one nitrogen heteroatom being adjacent to the connecting ring carbon atom. The preferred six-membered heteroaromatic rings include, ©" "forexample, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and tdazinyl. =~ ~~ ~~
During the course of the reaction the various functional groups such as the free carboxylic acid or hydroxy groups will be protected via conventional hydrolyzable ester or ether protecting groups. As used herein the term “hydrolyzable ester or ether protecting groups” designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective hydroxyl or carboxy! group. Exemplary ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane a. Co SR Se TI dicarboxcyclic acid. Among the activated acids which can be utilized to form such : groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Example of anhydndes are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxcyclic acid anhydrides, e.g. succinic anhydride as well as chloro formates e.g. trichloro, ethylchloro formate being preferred. A suitable ether protecting group for alcohols are, for example, the tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy- 2H-pyranyl ethers. Others are aroylmethylethers such as benzyl, benzhydryl or trityl ethers or o-lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethyisilylether.
The term “amino protecting group” designates any conventional amino protecting group which can be cleaved to yield the free amino group. The preferred protecting groups are the conventional amino protecting groups utilized in peptide synthesis.
Especially preferred are those amino protecting groups which are cleavable under mildly acidic conditions from about pH 2.0 to 3. Particularly preferred amino protecting groups are t-butoxycarbonyl (BOC), carbobenzyloxy (CBZ) and 9-flurorenylmethoxycarbonyl (FMOC).
The term “pharmaceutically acceptable salts” as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term “pharmaceutically acceptable salts” also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques.
~~ Woooss293 PCT/EP00/02450
In one preferable embodiment, the present invention relates to a compound comprising an amide of the above formula I, wherein
R' and R? are independently hydrogen, halo, amino, hydroxyamino, cyano, nitro, - = —-- lower alkyl, -OR?, -C(O)OR?, perfluoro-lower alkyl, lower alky! thio, perfluoro- SL lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or sulfonamido;
R’ is cycloalkyl having from 3 to 7 carbon atoms;
R* is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six- membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, -(CH,),-OR®, -(CH),-C(O)OR’, -(CHa),-C(O)NHR’, -C(0)-C(O)OR? or -(CH,),-NHR®; nis0,1,2,3or4;
R’ is hydrogen, lower alkyl, or perfluoro-lower alkyl; and
RC, R” and R® are independently hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof.
In another preferable emodiment the present invention relates to a compound comprising an amide of the above formula I, wherein
R' and R? are independently hydrogen, halo, amino, nitro, cyano, sulfonamido, lower alkyl, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl,
© WO 00/58293 PCT/EP00/02450
Ris cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms;
R* is -C(O)NHR*’;
R* is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl, -(CH2)a-C(O)OR? or -C(0)-(CHa),-C(O)OR’;
R’ and R® are hydrogen or lower alkyl; and nis0,1,2,3 or4; or a pharmaceutically acceptable salt thereof.
Preferable heteroaromatic residues in R* are unsubstituted or mono-substituted five- or six-membered heteroaromatic rings selected from the group consisting of
Lol thiazolyl, pyrdinyl, imidazolyl, isoxazolyl, oxazolyl, pyridazinyl, pyrimidinyl or
HE thiadiazolyl. Especially preferred are unsubstituted thiazolyl, unsubstituted pyridinyl or : pyridinyl substituted by halogen, lower alkyl, hydroxy lower alkyl or -C(O)OR’ , Wherein \ 15 Ris lower alkyl.
Preferable residues R*° in accordance with the present invention are lower alkyl or lower alkenyl.
Preferable residues R' in accordance with the present invention are hydrogen, halo, nitro and cyano, more preferable are hydrogen or halo.
Preferable residues R® in accordance with the present invention are hydrogen, lower alkyl sulfonyl, perfluoro-lower alkyl, perfluoro-lower alkyl sulfonyl, halo or -OR’ wherein R” is perfluoro-lower alkyl; more preferable are halo or lower alkyl sulfonyl.
Preferable residues R’ in accordance with the present invention are cyclopentyl, cyclohexyl or cycloheptyl, more preferable is cyclopentyl.
In the compounds described below, unless otherwise indicated, R* is a group -C(O)NHR™, wherein R*’ is as defined above.
Fo —
In certain of such compounds, R* of the amide is hydrogen, lower alkyl, or lower alkenyl. Such amides are preferred when R’ is cyclopentyl, especially when the amide is in the “R” configuration at the asymmetric carbon shown. me In certain amides of the above compound, R' and R’ of the amide are hydrogen. Co
Such an amide is 1-(3-cyclopentyl-2-phenyl-propionyl)-3-methyl-urea. In other of the above compounds, one of R' and R? is hydrogen and the other is cyano or halo.
Examples of such amides are: 1-[2-(3-chloro-phenyl)-3 cyclopentyl-propionyl]-3-methyl-urea; 1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea; 1-[2-(4-cyano-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea; 1-[2-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea.
In other amides of the above compound, R' and R® of the amide are each a independently halo (preferably chloro). Examples of such amides are: : [3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl}-urea; 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea; :
I-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea; 1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl}-urea; 1-allyl-3-[3-cyclopentyl-2(R)-(3, 4-dichloro-phenyl)-proprionyl]-urea; 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea; 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea; . 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl}-3-isopropyl-urea; 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-propyl-urea; 1-[3-cyclopentyl-2-(3 4-difluoro-phenyl)-propionyl]-3-methyl-urea. N
In yet other amides of the above compound, one of R'and R? of the amide is hydrogen or halo and the other is nitro. Examples of such amides are: 1-[2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea; 1-[3-cyclopentyl-2-(4-nitro-phenyl)-propionyl]}-3-methyl-urea. !
© WO 00/58293 PCT/EP00/02450
In further amides of the above compound, one of R' and R? is hydrogen, lower alkyl thio or perfluoro-lower alkyl thio and the other is lower alkyl thio or perfluoro-lower alkyl thio. Examples of such amides are: 1-[3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-propionyl}-3-methyl urea. _ In yet further amides of the above compound, one of R' and R? is hydrogen or = perfluoro-lower alkyl sulfonyl and the other is perfluoro-lower alkyl sulfonyl. Examples ’ of such amides are: 1-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea; 1-[3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea.
In certain amides of the above compound, at least one of R' and R? is lower alkyl sulfonyl. Preferably one of R' and R? is hydrogen or lower alkyl sulfonyl and the other is lower alkyl sulfonyl, and more preferably Ris lower alkyl sulfonyl. Examples of such amides are: 1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl}-3-methyl urea; 1-{2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-proprionyl }-3-methyl-urea; 1-[3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-proprionyl]-3-methyl-urea; 1-[2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl}-3-methyl-urea.
In other amides of the above compound, at least one of R' and R?* is lower alkyl sulfonyl, one of R' and R? is cyano or halo and the other, preferably R?, is lower alkyl sulfonyl. Examples of such amides are: 1-[2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl}-3-methyl-urea; 1-[3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-proprionyl}-3-methyl-urea; 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea; 1-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl}-3-methyl-urea; 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-ethyl-urea; 1-[2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionylj-3-methyl-urea.
In other amides of the above compound, at least one of R' and R” is lower alkyl sulfonyl, one of R' and R? is perfluoro-lower alkyl and the other, preferably R?, is lower alkyl sulfonyl. An Example of such an amide is 1-[3-cyclopentyl-2-(4-methanesulfonyl- 3-trifluoromethyl-phenyl)-proprionyl]-3-methyl-urea.
In further amides of the above compound, at least one of R' and R? is perfluoro- ~~. . . .. loweralkyl and the other is halo. Examples of such amides are: - : Co 1-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionyl}-3-methyl urea; 1-[3-cyclopentyl-2-(3-fluoro-4-trifluoromethyi-phenyl)-propionyl}-3-methyl urea.
In yet further amides of the above compound, at least one of R' and R? is lower alkyl sulfonyl, one of R' and R? is nitro and the other is lower alkyl sulfonyl. An example of such an amide is 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionyl]-3- methyl-urea.
In the compounds of this invention described above, R* of the amide is hydrogen, lower alkyl, or lower alkenyl and R’ is cyclopentyl. In the compounds described below, oo
R* is the same but R? is not cyclopentyl.
In certain such compounds, one of R' and R? is halo or hydrogen and the other is : hydrogen. An example of such an amide is [2-(4-chloro-phenyl)-4-methyl-pentanoyl]- urea. In particular R' and R? may each be chlorine. Examples of such amides are: [3-cyclopropyl-2-(3,4-dichloro-phenyl)-propionyl}-urea; [3-cyclobutyl-2-(3,4-dichloro-phenyl)-propionyl}-urea;
R-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]-urea; 1-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]}-3-methyl-urea; 1-[2-(3,4-dichloro-phenyl)-hexanoyl]}-3-methyl-urea.
In other such compounds, R* is as described above and R is cyclohexyl. In some such amides, one of R' and R? is halo or hydrogen and the other is halo. Examples of such amides are: 3-[cyclohexyl-2-(3,4-dichloro-phenyl)-propionyl]-urea; [3-cyclohexyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea.
In other such compounds, R* is as described above and R? is cycloheptyl. In some such amides, one of R' and R? is halo or hydrogen and the other is halo. An example of such an amide is [3-cycloheptyl-2-(3,4-dichloro-phenyl)-propionyl]-urea.
In certain. compounds of this invention, R* is -(CH,).-C(O)OR® or -C(0O)-(CH,),-C(O)OR®. In some such compounds, R> of the amide is cyclopentyl.
Preferably R' and R* are independently halo. Examples of the above amides are: 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido }-propionic acid ethyl ester; {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido } -acetic acid ethyl ester; © {3-(3-cyclopentyl-2-(3 4-dichloro-phenyl)-propionyl}-ureido} -acetic acid methyl ester; 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl}-ureido }-propionic acid methyl ester; {3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-ureido }-acetic acid ethyl ester; 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido } -3-oxo-propionic acid ethyl ester.
In certain compounds of this invention, R* is hydroxy lower alkyl, or halo lower : alkyl. In some such compounds, R* of the amide is cyclopentyl. Preferably R' and R? are
Eo 15 independently halo, and in addition the amide is in the “R” configuration at the to asymmetric carbon shown. Examples of the above amides are: son ~ 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl}-3-(2-hydrox y-ethyl)-urea; go 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydroxy-propyl)-urea;
K 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydrox y-propyl)-urea; 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydroxy-propyl)-urea; 1-(2-chloro-ethyl)-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propnionyl]-urea;
I-[3-cyclopentyl}-2(R)-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydroxy-propyl)-urea.
In the compounds described below, unless otherwise indicated, R* is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ning carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a
EY position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, -(CH2),-OR®, -(CH,)a-C(O)OR’, -(CH,),-C(O)NHRS, -C(0)-C(O)OR?, -(CH,),-NHR. — In certain of such compounds, R® is cyclopentyl (the compound I-D). The
Co 5 embodiments of the compound I-D are those compounds where R* is an unsubstituted thiazole (Compound I-D1). Among the various embodiments of the compound of I-D1 are included those compounds where: : a) one of R' and R? is hydrogen, halogen, perfluoro-lower alkyl and the other of said
R' and R? is halo or perfluoro-lower alkyl; b) one of R' and R? is amino, nitro, halo, nitro or hydrogen and the other of said R' and R’ is amino, cyano or nitro; ; c) one of R! and R? is lower alkylthio, perfluoro-lower alkyl thio, halo or hydrogen and the other of said R' and R? is perfluoro-lower alkylthio, lower alkylsulfinyl or lower alkylthio; d) one of R' and R* is lower alkyl sulfonyl, hydrogen, nitro, cyano, amino, hydroxyamino, sulfonamido or halo, and the other of said R' and R? is lower alkyl sulfonyl; e) one of R! and R? is lower alkyl sulfonyl, and the other of said R' and R? is halo or perfluoro-lower alkyl;
DH one of R' and R? is perfluoro-lower alkyl sulfonyl or hydrogen and the other of said R' and R? is perfluoro-lower alkyl sulfonyl; 2) one of R' and R? is -OR®, or -C(O)OR® and the other of said R' and R? is hydrogen or “OR: and R’ is as above; and Co ’ ’ h) one of R! and R? is -OR’® and the other is halo.
In accordance with another embodiment of this invention where R? is cyclopentyl, the embodiments are those compounds where R* is a mono-substituted thiazole (compounds I-D2). Among the embodiments of compounds I-D2, are those compounds where the mono-substitution 1s -(CH,),-OR® and n and R® are as above (compounds I-
D2(a)). Among the embodiments of compounds I-D2 (a) are those compounds where: a) one of R' and R? is halo and the other of said R' and R? is hydrogen or halo;
© WO 00/58293 PCT/EP00/02450 b) one of R' and R? is lower alkyl sulfonyl, and the other of said R! and R? is lower alkyl sulfonyl or hydrogen; and c) one of R' and R? is hydrogen and the other of said R' and R? is lower alkyl or perfluoro-lower alkyl.
In accordance with another embodiment of the invention where R> is cyclopentyl ~~ andR"is a mono-substituted thiazole (Compounds I-D2), are those compounds wherethe ~~ mono-substitution is lower alkyl and one of R' and R? are hydrogen or halogen and the other of R' and R? is halogen (Compounds I-D2(b)).
BN Among another embodiment of the compounds I-D are those compounds where the mono-substituted thiazole is substituted with -(CH,),-C(O)OR’, wherein n 1s 0 or 1 and R’ is hydrogen, or lower alkyl (Compounds of I-D2(c)). Among the embodiments of compounds of formula I-D2(c) are those compounds where: 2. a) one of R' and R? is hydrogen and the other of said R' and R? is halo;
L b) R' and R? are each independently halo; uw 15 ©¢) one of R' or R? is nitro, amino or hydrogen and the other of said R' and R? is nitro : or amino; and d) one of R' and R? is lower alkyl sulfonyl, perfluoro-lower alkyl, halogen or i E hydrogen and the other of said R' andR? is lower alkyl sulfonyl.
In accordance with another embodiment of this invention, where R® and cyclopentyl and R* is a mono-substituted thiazole (Compounds I-D2) are those compounds where the mono-substituted thiazole is substituted with -C(O)-C(O)OR?, wherein R® is as above (Compounds I-D2(d)). Among the embodiments of compound I-
D2(d) are those compounds where: a) one of R' and Rare hydrogen and the other of said R' and R* is nitro or amino; b) one of R! and R? is halo or perfluoro-lower alkyl and the other of said R! and R? 1s perfluoro-lower alkyl, halogen or hydrogen; and c) one of R' and R? is hydrogen or halogen and the other of said R' and R? is lower alkylsulfonyl.
em 4
In accordance with another embodiment of this invention, where R? is cyclopentyl and R* is a mono-substituted thiazole, compounds I-D2, are those compounds where the mono-substitution on the thiazole ring is a nitro group and one of R' and R? are hydrogen and halogen and the other of R' and R? is halogen or lower alkyl sulfonyl (compound of ) formulal-D2(e)).
In accordance with another embodiment of this invention, where R? is cyclopentyl (Compound I-D) and R* is an unsubstituted pyndine (Compounds I-D3). Among the embodiments of compound I-D3 are those compounds where: a) one of R' and R? are halo, perfluoro-lower alkyl or hydrogen and the other of said
R' and R? is halo, perfluoro-lower alkyl, amino, cyano or nitro; b) one of R' and R? is lower alkyl thio, perfluoro-lower alkyl thio or cyano, and the other is hydrogen; : - c) one of R! and R? is lower alkyl sulfonyl, halo, cyano, nitro or hydrogen and the other of said R' and R® is lower alkyl sulfonyl; and : d) one of R' and R? is perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl or hydrogen and the other of said R' and R? is perfluoro-lower alkyl sulfonyl or perfluoro-lower alkyl. | }
In accordance with another embodiment of the invention, where R> is cyclopentyl (Compounds I-D) are those compounds where R* is a mono-substituted pyridine ring.
Among the embodiments of the mono-substituted pyridine (Compounds I-D4) are those compounds where the mono-substitution is -(CH,),-C(O)OR’, wherein n and R are as above (compound I-D4(a)). Among the embodiments of compounds I-D4(a) are those oo compounds where: oo EE oo a) wherein R! and R? are each independently halo; b) wherein one of R' and R? is hydrogen and the other of said R' and R? is halo, amino, cyano or nitro; and
Cc) one of R' and R? is perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl or hydrogen and the other of said R' and R? is perfluoro-lower alkyl sulfonyl or lower alkyl! sulfonyl.
© Wo 00/58293 PCT/EP00/02450
Other embodiments of the compounds of formula I-D4(b) are those compounds where the pyridine ring is mono-substituted with -(CH,),-OR® wherein n and R® are as above (Compounds I-D4(b)). Among the embodiments of the compound I-D4(b) are those compounds where: . 5 a) one of R' and R? are halo and the other of said R' and R? is hydrogen or halo; and b) one of R' and R? is lower alkyl sulfonyl or hydrogen and the other of said R! and Risloweralkylsufonyl
Another embodiment of compounds where R’ is cyclopentyl and R* is a mono- substituted pyridine ring are those compounds where the pyndine ning 1s mono- substituted with a halo or perfluoro-lower alkyl substituent, the compound of formula I-
D4(c). Among the embodiments of the compound of formula I-D4(c) are those compounds where: a a) one of R' and R? is halo or hydrogen and the other is halo; and yo b) one of R' and R? is halo, nitro or hydrogen and the other is perfluoro-lower alkyl y 13 sulfonyl or lower alkyl sulfonyl.
Co In accordance with another embodiment of this invention are compounds of where - R’ is cyclopentyl and R* is a mono-substituted pyridine are those compounds where the : pyridine is mono-substituted with a nitro substituent, (Compound I-D4(d)). The embodiments of the compound I-D4(d) include compounds where one of R! and R? is halo and other of said R! or R? is hydrogen, halo, or lower alkyl sulfonyl.
In accordance with another embodiment of this invention are compounds of formula I where R? is cyclopentyl and R* is mono-substituted pyridine and the mono- substitution is a lower alkyl group (Compounds 1-D4(e)). Among the embodiments of compounds I-D4(e) are those compounds where one of R! and R? is halo or hydrogen and the other of R' and R? is halo, perfluoro-lower alkyl, perfluoro-lower alkyl sulfonyl, or lower alkyl sulfonyl.
In accordance with another embodiment of this invention where R? is cyclopentyl and R* is a mono-substituted pyridine are those compounds where the mono-substituent is -(CH3)a-C(0O)-NHR, wherein n and R are as above (Compound I-D4(f)). Among the
SESS —————— EP — embodiments of compound I-D4(f) are those compounds wherein one of R' and R* are independently selected from the group consisting of halo or hydrogen and the other of said R' and R? is halo, or lower alkyl sulfonyl. — Another embodiment of .this invention where R’ is cyclopentyl are those } 5S compounds where R* is an unsubstituted imidazolyl (Compound I-D5). Among the embodiments of compounds I-D5 are those compounds wherein one of R' and R? is selected from the group consisting of halo and hydrogen and the other of said R' and R?is : halo, or lower alkyl sulfonyl.
Another embodiment of the compounds of this invention are those compounds where R’ is cyclopentyl and R* is an isoxazolyl ring (the compound I[-D6). The embodiments of compound I-D6 are those compounds where the isoxazolyl ning is unsubstituted or substituted, preferably mono-substituted. Among the mono-substituted oo substituents, the preferred substituents substituted on the isoxazolyl ring is lower alkyl.
An embodiment of the compound I-D6, either where the isoxazolyl ring is unsubstituted or substituted with a Jower alkyl substituent are those compounds where one of R' and R? is halo, nitro, lower alkyl sulfonyl or perfluoro-lower alkyl and the other of R' and R? is : hydrogen or halo.
Another embodiment of this invention where R’ is cyclopentyl are those compounds where R* is either an unsubstituted oxazolyl, or an oxazolyl mono-substituted with a lower alkyl group. Another embodiment with respect to either of those compounds are those compounds where one of R! or R? is halo, nitro, lower alkyl sulfonyl or perfluoro-lower alkyl and the other is of R' or R? is hydrogen or halo. } :
Another embodiment of this invention where R® is cyclopentyl are those compounds where R* is pyridazinyl which is either unsubstituted or substituted with a lower alkyl group (Compound I-D7). Embodiments of the compound I-D7 are encompassed by this invention include those compounds where one of R' or R? is halo, nitro, lower alkyl sulfonyl or perfluoro-lower alkyl and the other of said R! or R? is hydrogen or halo.
© WO 00/58293 PCT/EP00/02450
Another embodiment of this invention where R’> is cyclopentyl include compounds where R* is unsubstituted pyrimidinyl. The embodiments of those compounds where R® is cyclopentyl and R* is unsubstituted pyrimidinyl include those compounds where one of R' or R? is halo, nitro, lower alkyl sulfonyl or perfluoro-lower alkyl and the other 1s hydrogen or halo.
Another embodiment of this invention includes compounds where R’ is cyclopentyl where R* is an unsubstituted thiadiazolyl ring. Among the embodiments included within those compounds where R’ is cyclopentyl and R* is an unsubstituted thiadiazolyl ring are those compounds wherein one of R! or R? is halo, nitro, lower alkyl sulfonyl or perfluoro-lower alkyl and the other of said R' and R* is hydrogen or halo.
In accordance with other embodiments of this invention, R® in the compound of formula I can be cycloheptyl or cyclohexyl. The embodiments of the compound of
Lo formula I where R® is cycloheptyl or cyclohexyl include those compounds where R* is
Boo oo thiazolyl which can be mono-substituted or unsubstituted. Embodiments included within
Co. 15 such compounds where R® is cycloheptyl or cyclohexyl and R* is an unsubstituted
I. thiazolyl include those compounds wherein one of R' and R? is halo, lower alkyl sulfinyl, perfluoro-lower alkyl sulfinyl, perfluoro-lower alkyl or lower alkyl sulfonyl and the other is of said R' and R? with halo, perfluoro-tower alkyl or hydrogen.
Examples of compounds of formula I according to the present invention, wherein
R* is a heteroaromatic ring are: 2-(3-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(4-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-phenyl)-propionamude, 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamude, 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide,
3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-thiazol-2-yl-propionamide, - 3-cyclopentyl-2-(4-nitrophenyl)-N-thiazol-2-yl-propionamide, 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(3-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide,
2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, oo 2-(4-cyano-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethylsuifanyl-phenyl)-propionamide, 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-
propionamide, 3-cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide, _ 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide,
3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl- propionamide, 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide, 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, :
3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide, 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-[4-(propane-1-sulfonyl)-phenyl]-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl- propionamide,
: - 25+. 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide,. Se. 2-[3-chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide, 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluvoromethanesulfonyl-phenyl)-propionamide,
3-cyclopentyl-N-thiazol-2-yi-2-(4-trifluoromethoxy-phenyl)-propionamide, 3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide,
© WoO 00/58293 PCT/EP00/02450 3-cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide, 4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic acid methyl ester,
S 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3-fluoro-4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide, 7 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-{4-(2-hydroxyethyl)-thiazol-2-yl]-propionamide, 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydrox ymethyl-thiazol-2-yl)-propionamude, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-propionamide, 3-cyclopentyl-N-(4-hydrox ymethyl-thiazol-2-y1)-2-(4-methanesulfonyl-phenyl)- propionamide, 3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl}-2-(4-methanesulfonyl-phenyl)- propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methyl-thiazol-2-yl)-propionamide, 3-cyclopentyl-2-(3.4-dichlorophenyl)-N-(5-methyl-thiazol-2-yl)-propionamide, {2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino}-thiazol-4-yl }-acetic acid ethyl ester, {2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl }-acetic acid methyl ester, 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester, 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester, {2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester, 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]}-thiazole-4-carboxylic acid methyl ester, 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester, {2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl } -acetic acid methyl ester, {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino}-thiazol-4-yl } -acetic acid, {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl } -acetic acid ethyl 33 ester,
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid, 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylic acid, {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino}-thiazol-4-yl }-acetic acid methyl ester, (2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylic - - acid methyl ester, : 2-[3-cyclopentyl-2-(3.4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid methyl ester, 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester, {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl } -acetic acid ethyl ester. {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl } -acetic acid methyl ester, 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester, 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester, {2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl }-acetic acid methyl ester, 2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester, {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylaminoj-thiazole-4-carboxylic acid ethyl ester, {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl }-4-acetic acid methyl ester, {2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionylamino}- : . . thiazol-4-yl}-acetic.acid-methyl.ester, : : 2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionylamino]- thiazole-4-carboxylic acid methyl ester, {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl } -oxo-acetic acid ethyl ester, {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino}thiazol-5-yl }-oxo-acetic ethyl ester, {2-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-thiazol-4-yl } - oxo-acetic acid ethyl ester,
© WoO 00158293 PCT/EP00/02450
{2-[2-(3-chloro-4-methanesuifonyl-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl }- oxo-acetic acid ethyl ester, :
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitro-thiazol-2-yl)-propionamide,
3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide,
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide,
3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-2-propionamide,
__ _ .._ _3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide, ~~. _ - 2-(3-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide, 2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide,
2-(4- cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide, 2-(4-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide, 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyndin-2-yl-propionamide, 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide, 2-(4-cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide,
. 15 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide, 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide,
; 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide, 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide,
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide,
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl- propionamide, 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide, 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide, 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide, 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyndin-2-yl-
propionamide, 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymethylpyridin)-2-yl-propionamide, 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester, 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid,
6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester, 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester, 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester, 6-{2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester,
6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid, “- 6-[2-(4-cyano-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid, 6-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino}-nicotinic acid methyl ester,
Co 5 6-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nicotinic acid, 6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic acid methyl ester, 3-cyclopentyl-2(R)-(3,4-dichloro-pheny!)-N-(5-hydroxymethyl-pyridin-2-yl)- propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propionamide, 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide, 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl)- propionamide,
N-(5-chloro-pynidin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide, : 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-brompyridin)-2-yl-propionamide, 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-yl)- : ~ propionamide,
N-(5-bromo-pynidin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide, :
N-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)- propionamide,
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)- propionamide,
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)- propionamide, 2-(3-bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl- propionamide,
N-(5- bromo-pyridin-2-yl)-2-(3-chloro-4-methanesuifonyl-phenyl)-3-cyclopentyl- propionamide, 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl-pyridin-2-yi)- : propionamide,
N-(5-chloro-pyrnidin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-nitropyridin)-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-methylpyridin)-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(4-methylpyridin)-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(6-methylpyridin)-2-yl-propionamide,
© WO 00/58293 PCT/EP00/02450 3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoromethanesulfonyl-phenyl)- propionamide, 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-methyl-pyridin-2-yl)- propionamide, 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide, ~ 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionamide, 3-cyclopentyl-2-(3.4-dichlorophenyl)-N-oxazol-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyndazin-3-yl-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-6-yl-propionamide, 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyrimidin-4-yl-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide, 2:[4-methanesulfonyl phenyl)-3-cyclohexyl N-thiazol-2-yl-propionamide, and i 15 2-[4-methanesulfony] phenyl}-3-cycloheptyl N-thiazol-2-yl-propionamide.
Examples of compounds of formula I according to the present invention, wherein oo R* is a residue -C(O)NHR* and R*’ is as defined above, are: 1-(3-cyclopentyl-2-phenyl-propionyl)-3-methyl-urea,
To 20 1-[2-(3-chloro-phenyl)-3 cyclopentyl-propionyl}-3-methyl-urea, 1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl}-3-methyl-urea, 1-[2-(4-cyano-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea, 1-{2-(4-bromo-phenyl)-3-cyclopentyl-propionyl}-3-methyl urea, (3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-urea, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea, 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea, 1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-urea, 1-allyl-3-[3-cyclopentyl-2(R)-(3, 4-dichloro-phenyl)-proprionyl]-urea, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea, 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-i1sopropyl-urea, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-propyl-urea,
— ye 1-[3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionyl]-3-methyl-urea, - = - 1-[2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea, 1-[3-cyclopentyl-2-(4-nitro-phenyl)-propionyl]-3-methyl-urea, 1-[3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)-propionyl}-3-methyl urea, 1-[3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl]-3-methyl urea, 1-{2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-proprionyl }-3-methyl-urea, 1-[3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-proprionyl]-3-methyl-urea, 1-[2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea, 1-[2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea, - : 1-[3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-proprionyl]-3-methyl-urea, 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea, I- [2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl}-3 -methyl-urea, 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-ethyl-urea, 1-[2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea, Co 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-proprionyl]-3-methyl- urea, 1-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionyl}-3-methyl urea, 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionyl]-3-methyl-urea, [2-(4-chloro-phenyl)-4-methyl-pentanoyl]-urea, [3-cyclopropyl-2-(3,4-dichloro-phenyl)-propionylj-urea, - 25 [3-cyclobutyl-2-(3 4-dichloro-phenyl)-propionyl}-urea, oo
R-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]}-urea, 1-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]-3-methyl-urea, 1-[2-(3,4-dichloro-phenyl)-hexanoyl]-3-methyl-urea, . 3-[cyclohexyl-2-(3,4-dichloro-phenyl)-propionyl}-urea, [3-cyclohexyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea, [3-cycloheptyl-2-(3,4-dichloro-phenyl)-propionyl]-urea, 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido }-propionic acid ethyl ester, :
{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido }-acetic acid ethyl ester, {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido }-acetic acid methyl ester, 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido } propionic acid methyl ester, {3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-ureido } -acetic acid ethyl ester, . 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido }-3-oxo-propionic acid ethyl ester, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydroxy-propyl)-urea, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydroxy-propyl)-urea, 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydrox y-propyl)-urea, 1-(2-chloro-ethyl)-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl}-urea, and 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydroxy-propyl)-urea.
N 15 It will be appreciated that the compounds of formula I may be derivatised at
N | functional groups to provide derivatives which are capable of conversion back to the . parent compounds in vivo. Additionally, any physiologically acceptable equivalents of the . ) compounds of formula I, which are capable of producing the parent compounds of formula I in vivo, are within the scope of this invention. = 20 E
The compound of formula I can be prepared starting from the compound of formula V by the following Reaction Scheme:
: Reaction Scheme
R
COOR" , —_ COOR™
R
I Coste Vo R-CH,X rR? : oo :
R vi ov
I
\/
Rr: 2 .
R XI
Rr yd 3 . ie ¥ | R42-NH, R [Vi ocH
NH \/ : 2 3
R 2 fo) . a RN TX
R]' IX ~R% R
R#1-N=C=0 | R HNCONH,
X ! R' i 3 a Y Id R :
H H No NH 2 ye Tr . Oo oO 2 oO © R :
R 1 Ib
R' : l-a } CIC(O)-(CH,),-C(O)OR® el. - CL : | Xm
R> \/
N N (CH,) OR®
YY TY i. 0 O © o 1
R I-c wherein R’, R? and R> are as above, R* is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, -(CHy),-OR®, -(CH,),-C(O)OR’, -(CH,),-C(O)NHR®, -C(0)-C(O)OR® or -(CH,),-NHR®, wherein R®, R7, R® and n are as defined above; R'is hydrogen or lower alkyl; and R* is lower alkyl, lower alkenyl, © hydroxy lower alkyl, halo lower alkyl or ~(CHy)-C(O)OR’®, wherein R® is hydrogen or lower alkyl and n is as defined above.
The carboxylic acids and their lower alkyl esters of formula V wherein one of R' and R? is nitro, cyano, thio, amino, chloro, bromo, or iodo and the other is hydrogen are commercially available. In cases, where only the carboxylic acids are available, they can be converted to the corresponding esters of lower alkyl alcohols using any conventional ; esterification methods. All the reactions hereto forward are to be carried out on lower alkyl esters of the carboxylic acids of formula V. The amino substituted compounds of . 15 formula V can be converted to other substituents either before or after conversion to the compounds of formulae I-a, Ib, I-c or I-d. In this respect, the amino groups can be diazotized to yield the corresponding diazonium compound, which in situ can be reacted with the desired lower alkyl thiol, perfluoro-lower alkyl thiol (see for example, Baleja,
J.D. Synth. Comm. 1984, 14, 215; Giam, C. S.; Kikukawa, K., J. Chem. Soc, Chem.
Comm. 1980, 756; Kau, D.; Krushniski, J. H., Robertson, D. W, J. Labelled Compd Rad. 1985, 22, 1045; Oade, S.; Shinhama, K.; Kim, Y. H., Bull Chem Soc. Jpn. 1980, 53, 2023; Baker, B. R.; et al, J. Org. Chem. 1952, 17, 164), or alkaline earth metal cyanide, to yield corresponding compounds of formula V, where one of the substituents is lower alkyl thio, perfluoro-lower alkyl thio, or cyano, and the other is hydrogen. If desired, the lower alkyl thio or perfluoro-lower alkyl thio compounds can then be converted to the corresponding lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl substituted compounds of formula V by oxidation. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion.
If it is desired to produce compounds of formula V wherein one of R' and R%is a lower alkyl or perfluoro-lower alkyl group, the corresponding halo substituted compounds ee of formula V can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding alkyl group (see for example, Katayama, T.;
Umeno, M., Chem. Lett. 1991, 2073; Reddy, G. S.; Tam., Organometallics, 1984, 3, 630; oo Novak, J; Salemink, C. A, Synthesis, 1983, 7, 597; Eapen, K. C.; Dua, S. S; }
Tamboroski, C., J. Org. Chem. 1984, 49, 478; Chen, Q, -Y.; Duan, J. =X. J. Chem. Soc.
Chem. Comm. 1993, 1389; Clark, J. H.; McClinton, M. A.; Jone, C. W.; Landon, P.;
Bisohp, D.; Blade, R. J., Tetrahedron Lert. 1989, 2133; Powell, R. L.; Heaton, C. A, US patent 5113013) can be utilized to effect this conversion. On the other hand, the thio substituent can be oxidized to a -SOsH group which then can be converted to -SO,Cl which is reacted with ammonia to form the sulfonamide substituent -S(O),-NH,. If it is desired to produce compounds of formula V wherein one or both of R! and R? is hydroxyamino, the corresponding nitro compounds can be used as starting material and can be converted to the corresponding compounds where R' and/or R? are hydroxyamino.
Any conventional method of converting a nitro group to the corresponding aromatic hydroxyamino compound can be used to affect this conversion.
The carboxylic acids or lower alkyl esters of formula V wherein both of R! and R? are chloro or fluoro are commercially available. In cases, where only the carboxylic acids are available, they can converted to the corresponding esters of lower alkyl alcohols using any conventional esterification method. To produce the compound of formula V where both R! and R? are nitro, 3,4-dinitrotoluene can be used as starting material. This compound can be converted to the corresponding 3,4-dinitrophenyl acetic acid. This conversion can take place either before or after the compound of formula V is converted to the compounds of formulae I-a, I-b, I-c or I-d. Any conventional method of converting ) ) an aryl methyl group to the corresponding aryl acetic acid can be utilized to effect this conversion (see for example, Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L.
A.; Repke, D. B.; Souchet, M, Synthesis, 1991, 871). The compounds of formula V where both R' and R? substituents are amino can be obtained from the corresponding dinitro compound of formula V, described above. Any conventional method of reducing a nitro group to an amine can be utilized to effect this conversion. The compound of formula V where both R! and R? are amine groups can be used to prepare the
© WO 00/58293 PCT/EP00/02450 corresponding compound of formula V where both R! and R? are iodine or bromine via a diazotization reaction. Any conventional method of converting amino group to an iodo or bromo group (see for example, Lucas, H. J.; Kennedy, E. R. Org. Synth. Coll. Vol, II 1943, 351) can be utilized to effect this conversion. If it is desired to produce compounds
S of formula V, where both R' and R? are lower alkyl thio or perfluoro-lower alkyl thio ~~ 7 ~~ groups, the compound of formula V where R' and R® are amino can be used as starting material. Any conventional method of converting aryl amino group to aryl thioalkyl group can be utilized to effect this conversion. If it is desired to produce compounds of formula
V where R' and R? are lower alkyl sulfonyl or lower perfluoro alkyl sulfonyl, the corresponding compounds of formula V where R' and R? are lower alkyl thio or perfluoro-lower alkyl thio can be used as starting material. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion.
If it is desired to produce compounds of formula V, where both R! and R? are substituted with lower alkyl or perfluoro-lower alkyl groups, the corresponding halo substituted compounds of formula V can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding alkyl or perfluoro- lower alkyl group can be utilized to effect this conversion.
If it is desired to produce compounds of formula V, where one or both of R' and
R? are substituted with sulfonamido, the corresponding compounds where one or both of
R' and R? are substituted with nitro can be used as starting materials. Any standard method of converting a nitrophenyl compound to the corresponding sulfonamidophenyl compound can be used to effect this conversion.
The carboxylic acids corresponding to the compounds of formula V where one of
R' and R? is nitro and the other is halo are known from the literature (see for 4-chloro-3- nitrophenyl acetic acid, Tadayuki, S.; Hiroki, M.; Shinji, U.; Mitsuhiro, S. Japanese patent, JP 71-99504, Chemical Abstracts 80:59716; see for 4-nitro-3-chlorophenyl acetic acid, Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Rousssi, G. J. Org. Chem. 1995, 60, 6389; Beugelmans, R.; Bourdet, S.; Zhu, J. Tetrahedron Lett. 1995, 36, 1279). These carboxylic acids can be converted to the corresponding lower alkyl esters using any
WOo00/58293 TERRES conventional esterification methods. Thus, if it is desired to produce the compound of formula V where one of R' and R? is nitro and the other is lower alkyl thio or perfluoro- lower alkyl thio, the corresponding compound where one of R' and R? is nitro and the i _ other is chloro can be used as starting material. In this reaction; any conventional method of nucleophilic displacement of aromatic chlorine group with a lower alkyl thiol can be used (see for example, Singh, P.; Batra, M. S.; Singh, H, J. Chem. Res.-S 1985 (6), S204;
Ono, M.; Nakamura, Y.; Sata, S.; Itoh, I, Chem. Lett, 1988, 1393; Wohrle, D.; Eskes, M.;
Shigehara, K.; Yamada, A, Synthesis, 1993, 194; Sutter, M.; Kunz, W, US patent, US : 5169951). Once the compounds of formula V where one of R' and R? is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio are available, they can be converted to the corresponding compounds of formula V where one of R' and R? is nitro and the . other is lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl using conventional oxidation procedures.
If it is desired to produce compounds of formula V where one of R' and R?is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding ~ compound where one of R! and R? is nitro and the other is lower alkyl thio or perfluoro- lower alkyl thio can be used as starting materials. Any conventional method of reducing an aromatic nitro group to an amine can be utilized to effect this conversion.
If it is desired to produce compounds of formula V where one of R' and R? is lower alkyl thio and the other is perfluoro-lower alkyl thio, the corresponding compound where one of R! and R? is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of diazotizing aromatic amino group and reacting it in sizu with the desired lower alkyl thiol can be utilized to effect this conversion.
If it is desired to produce compounds of formula V where one of R' and Ris lower alkyl sulfonyl and the other is perfluoro-lower alkyl sulfonyl, the corresponding compounds where one of R' and R? is lower alkyl thio and the other is perfluoro-lower alkyl thio, can be used as starting materials. Any conventional method of oxidizing an i WO 00/58293 PCT/EP00/02450 aromatic thio ether group to the corresponding sulfone group can be utilized to effect this conversion.
If it is desired to produce compounds of formula V where one of R' and R? is halo and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compounds where one of R' and R? is amino and the other is lower alkyl thio or
TT ~ perfluoro-lower alkyl thio can be used as starting materials: Any conventional method of diazotizing an aromatic amino group and conversion of it in sifu to an aromatic halide can be utilized to effect this conversion.
If it is desired to produce compounds of formula V where one of R' and R? is halo and the other is lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl, the corresponding compounds where one of R! and R? is halo and the other is lower alkyl thio or perfluoro- ; lower alkyl thio can be used as starting materials. Any conventional method of oxidizing an aromatic thio ether to the corresponding sulfone can be utilized to effect this ¥ conversion. If it is desired to produce compounds of various combinations of lower alkyl and perfluoro-lower alkyl groups of compounds of formula V, the corresponding halo . ‘substituted compounds of formula V can be used as starting materials. Any conventional ; method of converting an aromatic halo group to the corresponding alkyl group can be - utilized to effect this conversion.
If one wishes to prepare the compound formula V where one of R! and R? is nitro and the other is amino, the compound of formula V where one of R' and R? is nitro and other is chloro can be used as a starting material. The chloro substituent on the phenyl ring can be converted to an iodo substituent (see for example, Bunnett, J. F.; Conner, R.
M.; Org. Synth. Coll Vol V, 1973, 478; Clark, J. H.; Jones, C. W. J. Chem. Soc. Chem. : Commun. 1987, 1409), which in turn can be reacted with an azide transferring agent to form the corresponding azide (see for example, Suzuki, H.; Miyoshi, K.; Shinoda, M.
Bull. Chem. Soc. Jpn, 1980, 53, 1765). This azide can then be reduced in a conventional manner to form the amine substituent by reducing it with commonly used reducing agent for converting azides to amines (see for example, Soai, K.; Yokoyama, S.; Ookawa, A.
Synthesis, 1987, 48).
In order to prepare the compound of formula V where one of R' and R? is cyano and the other is amino, the compound of formula V where one of R' and R? is nitro and other is amino can be used as a starting material. The amino group is converted to cyano by conventional means of converting aryl-amino to aryl-cyano, for example by i 5 diazotization with a cyanide-transferring agent such as cuprous cyanide. The nitro group is converted to an amino group as described above.
If it is desired to convert commercially available compounds to compounds of formula V where one of R' and R? is cyano and the other is any other desired substituent as defined above, the compound of formula V where one of R! and R? is nitro and the . other is halo is used as starting material. With this starting material, the nitro is converted to the cyano and the halo is converted to the desired R' or R? substituent. } If it is desired to produce the compound of formula V where both R' and R? are cyano, this can be prepared as described hereinbefore from compounds where R' and R? are amino via diazotization and reaction with a cyanide-transferring agent such as cuprous cyanide. 0 If it is desired to produce the compound of formula V wherein one of R' or R? is -C(O)OR’, this compound can be formed from the corresponding compound where R! : and R? is an amino group by converting the amino group to a diazonium salt reacting the diazonium salt with a hydrohalic acid to form the corresponding halide and then reacting this halide with a Grignard reagent to produce the corresponding acid which can be esterified. On the other hand, if one wants to produce the compound of formula V where both R' and R? are carboxylic acid groups. This'compound can be produced as described above from the corresponding compound of formula V where both R' and R? are amino groups. In the same manner, the amino groups in the compound of formula V can be converted to the corresponding compound where R' or both of R! or R? is -OR® by simply reacting the amino group with sodium nitrate in sulfuric acid to convert the amino group to a hydroxy group and thereafter etherifying, if desired, the hydroxy group. :
The substituents which form R' and R? can be added to the ring after conversion of the compound of formula XI to the compounds of formulae I-a, I-b, I-c or I-d. Hence,
"WoO 00/58293 PCT/EP00/02450 all of the reactions described to produce various substituents of R' and R’ in the compound of formula I can also be carried out on the compounds of formulae I-a, I-b I-c or I-d.
In the first step of this Reaction Scheme, the alkyl halide of formula VI is reacted with the compound of formula V, fo produce the compound of formala VIL “In this - reaction, if in the compounds of formula V, R' or R? is an amino group, such amino group(s) have to be protected before carrying out the alkylation reaction with the alkyl halide of formula VI. The amino group can be protected with any conventional acid removable group (for example, for t-butyloxycarbonyl group see, Bodanszky, M.
Principles of Peptide Chemistry, Springer —Verlag, New York, 1984, p 99). The 0 protecting group has to be removed from the amino groups after preparing the vo corresponding amine protected compounds of formulae I-a, I-b, I-c or I-d to obtain the a corresponding amines. The compound of formula V is an organic acid having an alpha carbon atom and the compound of formula VI is an alkyl halide so that alkylation occurs i at the alpha carbon atom of this carboxylic acid. This reaction is carried out by any conventional means of alkylation of the alpha carbon atom of a lower alkyl ester of a : carboxylic acid. Generally, in these alkylation reactions any alkyl halide is reacted with the anion generated from any acetic acid ester. The anion can be generated by using a strong organic base such as lithium diisopropylamide, n-butyl lithium as well as other organic lithium bases. In carrying out this reaction, low boiling ether solvents are utilized such as tetrahydrofuran at low temperatures from -80°C to about -10°C being preferred.
However, any temperature from -80°C to room temperature can be used.
The compound of formula VII can be converted to the compound of formula XII by any conventional procedure to convert a carboxylic acid ester to an acid. The compound of formula XII can then be condensed with the compound of formula VIII via conventional peptide coupling to produce the compound of formula I-d. In carrying out this reaction, any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion. The required amino heteroaromatic woowssws pemEROOOMSY compounds of formula VIII, are commercially available or can be prepared from the reported literature. The heteroaromatics of formula VIII, wherein one of the substitutions is —(CH,),COOR’, where n = 0, 1, 2, 3, or 4 can be prepared from the corresponding carboxylic acid. Any conventional carbon homologation methods to convert a lower carboxylic acid to its higher homologs, (see for example, Skeean, R. W.; Goel, O. P.
Synthesis, 1990, 628) which then can be converted to the corresponding lower alkyl esters using any conventional esterification methods can be utilized. The heteroaromatics of formula VIII, wherein one of the claimed substitutions is -(CH,) LORS, wheren=0, 1, 2, 3, or 4 can be prepared from the corresponding carboxylic acid. Any conventional carbon homologation methods to convert a lower carboxylic acid to its higher homologs, which then can be converted to the corresponding alcohols using any conventional ester reduction methods can be utilized. The heteroaromatics of formula VIII, wherein one of the substituents is -COCOOR®, can be prepared from the corresponding halogen. Any conventional acylation method to convert an aromatic or heteroaromatic halogen to its oxoacetic acid lower ester derivative (see for example, Hayakawa, K.; Yasukouchi, T.;
Kanematsu, K. Tetrahedron Lett, 1987, 28, 5895) can be utilized. So
On the other hand, the carboxylic acid of the formula XII can be converted to the : amide of the formula IX. This reaction is carried out by using conventional means for converting the acid of formula XII to an acid chloride and thereafter treating this acid chloride with ammonia or an ammonia-producing compound such as hexamethyl disilazane. Conditions which are conventional for converting an acid to an acid chloride can be utilized in this procedure. This acid chloride when reacted under conventional . - © © 7 7 conditions with ammonia as described will produce the amide of formula IX. The compound of formula IX when reacted with an alkyl, alkenyl, or —~(CH,),C(O)OR? isocyanate of formula X forms the urea adduct of formula I-a. Any conventional method of reacting alkyl, alkenyl, or —(CH,),C(O)OR’® isocyanate with an amide to form a urea linkage can be utilized to form the compound of formula I-a.
SP Se TREE See ee
© WO 00/58293 PCT/EP00/02450
When R*! is a lower alkenyl group in the compound of formula I-a, this compound can be converted to the corresponding hydroxy lower alkyl group by conventional hydroboration at the olefinic group to produce a corresponding hydroxy group. The hydroxy group, if desired, can be converted to a halo group. Any method of halogenating ahydroxy group can be used in accordance with this invention. 77 7 On the other hand; if it is desired-to produce the-compound of formula I-b_the. _ compound of formula XII is first converted to the methyl ester of formula XI, and thereafter reacted with urea to produce the compound of forumula I-b. This reaction is carried out by utilizing any conventional means of reacting a methyl ester with urea to form the corresponding condensation product.
The compound of formula I-c, i.e. the compound of formula I wherein R* % -C(O)NHR* and R* is -CO-(CH,),-C(O)OR®, is produced from the monoacid chloride : Xm of the monoester of the corresponding dicarboxylic acid. The monoacid chloride ) XIII is coupled with the compounds of formula I-b using standard coupling methods.
The compound of formula VII has an asymmetric carbon atom through which the . group -CH,R’ and the acid amide substituents are connected. In accordance with this : invention, the preferred stereoconfiguration of this group is R. : If it 1s desired to produce the R or the S isomer of the compound of formula I, this compound can be separated into these isomers by any conventional chemical means.
Among the preferred chemical means is to react the compound of formula XII with an optically active base. Any conventional optically active base can be utilized to carry out this resolution. Among the preferred optically active bases are the optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha- methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction.
In the resolution step, the compound of formula XII is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of the compound of formula XII. In the formation of these salts, temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure. The R and S salts can be separated by any conventional method such as fractional crystallization. After crystallization, each of the salts can be converted to the respective compounds of formula XII in the R and S configuration by hydrolysis with an acid. Among the preferred acids are dilute aqueous acids, 1.e., from about 0.00IN to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid. The configuration of formula XII which is produced by this method of resolution 1s carried out throughout the entire reaction scheme to produce the desired R or
S isomer of formula I. The separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters corresponding to the compound of the formula XII (see for example, Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. )
The ester and the acid can be separated by any conventional method of separating an acid : from an ester. The preferred method of resolution of racemates of the compounds of the formula XII is via the formation of corresponding diastereomeric esters or amides. These diastereomeric esters or amides can be prepared by coupling the carboxylic acids of the formula XII with a chiral alcohol, or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine.
The corresponding diastereomers of compounds of the formula XII can then be separated using any conventional separation methods. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R or S isomers. The hydrolysis reaction can be carried out using conventional known methods to hydrolyze an ‘ester or an amide without racemization.
All of the compounds of formula I which include the compounds set forth in the
Examples, activated glucokinase in vitro by the procedure of Example A. In this manner, they increase the flux of glucose metabolism which causes increased insulin secretion.
Therefore, the compounds of formula I are glucokinase activators useful for increasing insulin secretion.
© WO 00/58293 PCT/EP00/02450
The following compounds were tested and found to have excellent glucokinase activator in vivo activity when administered orally in accordance with the assay described in Example B: 3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide; 3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide; —— — — 3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide; 3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide; 6-[3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester;
N-(5-Chloro-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide; 3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide; 3-Cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trnifluoromethanesulfonyl-phenyl)- propionamide; # 3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyrdin-2-yl) : 15 propionamide; ) 6-[{3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nicotinic acid methyl ester; 3-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide; 3-Cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyndin-2-yl-propionamide; ‘ 20 2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide; 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide; 2-(4-Chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyndin-2-yl-propionamide; 2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide:
N-(5-Bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- propionamide; 2-[3-Chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide; (2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide; 2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide; 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide; 3-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide; 3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl- propionamide; and
N-(5-Bromo-pyndin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- propionamide.
woowsmes _ per/moonmss—
Furthermore, the following compounds were tested and found to have excellent glucokinase activator in vivo activity when administered orally in accordance with the ~~ assay described in Example B: : : : 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea; 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea; 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl urea; 1-[3-cyclopentyl-2-(4-methanesulfony!l-phenyl)-propionyl]-3-methyl urea; 1-Allyl-3-{3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl}-urea; 1-[2-(3-Chloro-4-methanesuifonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea; 1-[2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl}-3-methyl-urea; and 1-[2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea. :
On the basis of their capability of activating glucokinase, the compounds of Fo formula I can be used as medicaments for the treatment of type II diabetes. Therefore, as. mentioned earlier, medicaments containing a compound of formula I are also an object of - the present invention, as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula I and, if desired, one or : more other therapeutically valuable substances into a galenical administration form.
The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragées, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example - using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally, using for example injectable solutions. Furthermore, administration can be carried out sublingually or as an aerosol, for example in the form of a spray. For the preparation of tablets, coated tablets, dragées or hard gelatine capsules the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragées or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc.; according to the nature of the active ingredients it may however be the case that no excipient is needed at all for soft gelatine capsules. For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose. For injectable solutions, excipients which may be used include for example water, alcohols, polyols, glycerine, and vegetable ols. | For suppositories, and local or percutaneous application, excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols. :
The pharmaceutical compositions may also contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. As mentioned earlier, they may also contain other therapeutically valuable agents. It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic.
Preferred forms of use are intravenous, intramuscular or oral administration, most preferred is oral administration. The dosages in which the compounds of formula (I) are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of application. In general, dosages of about 1-100 mg/kg body weight per day come into consideration.
This invention will be better understood from the following examples, which are for purpose of illustration and are not intended to limit the invention defined in the claims that follow thereafter.
ee
Example 1 (A) 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide:
H H
“7 N o 0) [7
Cl
A solution of 3-cyclopentyl-2-(3.4-dichlorophenyl)-propionic acid (prepared in Example 38, 20 g 6.96 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (4.62 g, 10.44 mmol), and 2-aminothiazole (1.05 g, 10.44 mmol) in methylene chloride (50 mL) at 25°C was treated with triethylamine (2.9 mL, 20.88 mmol). The reaction mixture was stirred for 14 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3 x 10 mL). The combined organic layers were sequentially washed with water (1 x 10 mL), a IN aqueous sodium hydroxide solution (1 x 10 mL), a IN aqueous hydrochloric acid solution (1 x 10 mL), . and a saturated aqueous sodium chloride solution (1 x 10 mL). The organic layer was dried over sodium sulfate, . filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl- 2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide (2.48 g, 96%) as a white solid: mp 143.5-145.5°C; EI-HRMS m/e calcd for C;7H;5C1L,N,0S (M™) 368.0516, found 368.0516. (B) In an analogous manner, there were obtained: (a) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and 2-(amino-thiazol-4-yl)- oxo-acetic acid ethyl ester: {2-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]- thiazol-4-yl}-oxo-acetic acid ethyl ester as a white solid: mp 134-136°C; FAB-HRMS m/e calcd for C;;H25ClN,04S (M+H) 469.0755, found 469.0746. (b) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and 2-(amino-thiazol-5-yl)- oxo-acetic acid ethyl ester: {2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-
B wo 00/58293 PCT/EP00/02450 thiazol-5-yl}-oxo-acetic acid ethyl ester as a white solid: mp 129-131°C; FAB-HRMS m/e calcd for Cy; Hp,C1LN,0,S (M+H)" 469.0755, found 469.0765. (c) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and (2-amino-thiazol-4-yl)- acetic acid ethyl ester: {2-[3-Cyclopentyl-2-(3,4-dichloropheny!)-propionylamino]- thiazol-4-yl}-acetic acid ethyl ester as a yellow solid: mp 138-139°C; FAB-HRMS m/e calcd for Co Hs CILN,OsS (M+H)' 455.0963, found 455.0960. (d) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and 2-amino-5- methylthiazole: 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-thiazol-2-yl)- propionamide as a white solid: mp 142-143°C; EI-HRMS m/e calcd for C;3H,0C1N,OS (M™) 382.0673, found 382.0679. (e) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and 2-amino-4- methylthiazole: 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methyl-thiazol-2-yl)- vo propionamide as a white foam: mp 151-152°C; FAB-HRMS m/e calcd for
Co C18H20C1,N,0S (M+H)™ 383.0751, found 383.0758. . 15 (f) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and 2-amino-thiazole-4- . g carboxylic acid ethyl ester: 2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino}- : thiazole-4-carboxylic acid ethyl ester as a white solid: mp 104-107°C; FAB-HRMS m/e calcd for CoH,CIoN,05S (M+H)™ 441.0807, found 441.0808. (g) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and 2-amino-thiazole-5- carboxylic acid ethyl ester: 2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]- thiazole-5-carboxylic acid ethyl ester as a light yellow solid: mp 136-137°C; FAB-HRMS m/e calcd for CoH,ClN,05S (M+H)™ 441.0807, found 441.0803. (h) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and 2-amino-5- nitrothiazole: 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitro-thiazol-2-yl)- propionamide as an orange solid: mp 67-71°C; FAB-HRMS m/e calcd for
C,7H7CI:N3058 M+H)" 414.0446, found 414.0442. (1) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and 2-amino-thiazole-4- carboxylic acid amide: 2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-
— thiazole-4-carboxylic acid amide as a light orange solid: mp 120-122°C; EI-HRMS m/e calcd for C,3H,0C1oN;30,S (M™) 411.0575, found 411.0572. - B Example 2 i oo 2-(4-Bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
H
“7 . 0 Z)
A solution of diisopropylamine (7.7 mL, 54.88 mmol) in dry tetrahydrofuran (23 mL) and - 1,3-dimethyl-3.,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to -78°C under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (22.0 mL, 54.88 mmol). The resulting reaction mixture was stirred at -78°C for 30 min and then treated dropwise with a solution of 4-bromophenylacetic acid (5.62 g, 26.13 mmol) in dry tetrahydrofuran (23 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The reaction mixture turned dark in color and was allowed to stir at -78°C for 1 h, at which time, a solution of iodomethylcyclopentane (5.76 g, 27.44 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25°C where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified using a 10% aqueous hydrochloric acid solution. The resulting aqueous i h layer was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 2-(4-bromo- phenyl)-3-cyclopentyl-propionic acid (3.88 g, 50%) as a light yellow solid: mp 91-93°C;
EI-HRMS m/e calcd for Cy,H;7BrO, (M") 296.0412, found 296.0417.
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid (1.01 g, 3.39 mmol) in methylene chloride (8.5 mL) was treated with 2 drops of dry N,N-dimethylformamide.
The reaction mixture was cooled to 0°C and then treated with oxalyl chloride (3 mL, 33.98 mmol). The reaction mixture was stirred at 0°C for 10 min and then stirred at 25°C : 5 for 15 h. The reaction mixture was concentrated in vacuo. The resulting yellow oil was dissolved in a small amount of methylene chloride and slowly added to a cooled solution oo oo (0°C) of 2-aminothiazole (680.6 mg, 6.79 mmol) and N,N-diisopropylethylamine (1.2 mL. 6.79 mmol) in methylene chloride (17 mL). The resulting reaction mixture was stirred at 0°C for 10 min and then at 25°C for 15 h. The reaction mixture was concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a 10% aqueous hydrochloric acid solution (2 x 100 mL), washed with a saturated aqueous sodium so : bicarbonate solution (2 x 100 mL), and washed with a saturated aqueous sodium chloride fo solution (1 x 100 mL). The organic layer was then dried over sodium sulfate, filtered, and oo 15 concentrated in vacuo to afford 2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl- - Ny propionamide (1.23 g, 95%) as an orange solid which was used in subsequent reactions . ) | without further purification. An analytical sample was recrystallized from ethyl acetate to : provide a cream solid: mp 201-202°C; EI-HRMS m/e calcd for C;7H;9BrN,OS (MH 378.0401, found 378.0405.
Example 3 (A) 3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide hg 3 SW o=7y
CH,
i. WO 00/58293 PCT/EPOOO24S0 -_—
A solution of diisopropylamine (3.3 mL, 23.5 mmol) in dry tetrahydrofuran (50 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to -78°C under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.35 mL, 23.5 mmol). The yellow reaction mixture was stirred at -78°C for 30 min and then treated dropwise with a solution of 4-methylsulfonylphenylacetic acid (2.40 g, 11.2 mmol) in a small amount of dry tetrahydrofuran. After approximately one-half of the 4- methylsulfonylphenylacetic acid in dry tetrahydrofuran was added, a precipitate formed.
Upon further addition of the remaining 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reaction mixture became thick in nature. After complete addition of the 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reaction mixture was very thick and became difficult to stir. An additional amount of dry tetrahydrofuran (20 ml) was added to the thick reaction mixture, and the reaction mixture was stirred at - 78°C for 45 min, at which time, a solution of iodomethylcyclopentane (2.35 g, 11.2 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25°C where it was stirred for 15 h. The reaction mixture was quenched with water (100 mL), and the resulting yellow reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified to pH = 2 using concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (1.80 g, 52%) as a white solid: mp 152-154°C; EI-HRMS m/e calcd for C;sH2004S (M") 296.1082, found 296.1080. ~ oT TT SE
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (4.91 g, 16.56 mmol) and triphenylphosphine (6.52 g, 24.85 mmol) in methylene chloride (41 mL) was cooled to 0°C and then treated with N-bromosuccinimide (5.01 g, 28.16 mmol) in small portions. The reaction mixture color changed from light yellow to a darker yellow then to brown. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25°C over 30 min. The brown reaction mixture was then treated with 2-aminothiazole (4.98 g, 49.69 mmol). The resulting reaction mixture was stirred at 25°C for 19 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with a 10% aqueous hydrochloric acid oo 5 solution (400 mL) and then extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1 x 200 oo chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2- - 10 yl-propionamide (4.49 g, 72%) as a white solid: mp 216-217°C; EI-HRMS m/e calcd for
Ci18H22N>05S, (M7) 378.1072, found 378.1071.
HE (B) In an analogous manner, there were obtained: (a) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid and 2- } 15 aminothiazole-4-carboxylic acid methyl ester: 2-[3-Cyclopentyl-2-(4-methanesulfonyl- i phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester as a tan solid: mp 126- } 128°C; EI-HRMS m/e calcd for CooH4N,05S,; (M") 436.1127, found 436.1119. (b) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid and 2- aminothiazole-4-carboxylic acid ethyl ester: 2-[3-Cyclopentyl-2-(4-methanesulfonyl- phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester as a light yellow solid: mp 101-103°C; EI-HRMS mye calcd for C1 Ha6N>OsS, (M™) 450.1283, found 450.1284. (c) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid and methyl 2- amino-4 thiazoleacetate: {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)- propionylamino]-thiazol-4-yl }-acetic acid methyl ester as a yellow solid: mp 63-65°C; EI-
HRMS m/e calcd for Cp Ha6N,0sS; (M™) 450.1283, found 450.1294. (d) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid and ethyl 2-amino- 4-thiazoleacetate: {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-
thiazol-4-yl}-acetic acid ethyl ester as a light yellow solid: mp 61-63°C; EI-HRMS m/e calcd for CH2sN,05S, (MM 464. 1440, found 464.1431. oo I Example 4 oo 2-(4-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
H
H
N
Jes 0 S
HoN
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide (prepared in
Example 22, 345 mg, 1.0 mmol) in ethyl acetate (100 mL) was treated with 10% palladium on activated carbon (34.5 mg). The reaction mixture was stirred under hydrogen gas at 60 psi at 25°C for 6 h. The catalyst was then filtered off through a pad of celite (ethyl acetate). The filtrate was concentrated in vacuo to give 2-(4-amino-phenyl)- 3-cyclopentyl-N-thiazol-2-yl-propionamide (288.3 mg, 91.4%) as a yellow solid: mp 102- 107°C; EI-HRMS m/e calcd for C17H;N50S (M*) 315.1405, found 315.1401.
Example 5 2-(3-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
H H
N N
TT)
NH,
A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) in methanol (50 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 48
© wo 00/58293 PCT/EP00/02450 h. The reaction was then concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (2 x 25 mL), water (1 x 50 mL), and a saturated aqueous sodium chloride solution (1 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp 29-30°C; EI-HRMS m/e calcd for CoHoNO4 (M™) 195.0531, “found 1950532.
A solution of freshly prepared lithium diisopropylamide (43.3 mL of a 0.3M stock solution, 12.99 mmol) cooled to -78°C was treated with (3-nitro-phenyl)-acetic acid methyl ester (2.45 g, 12.56 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro- 2(1H)-pyrimidinone (32 mL, 3:1). The resulting solution was stirred at -78°C for 45 min.
Todomethylcyclopentane (2.78 g, 13.23 mmol) was then added in 1,3-dimethyl-3,4,5,6- tetrahydro-2(1H)-pyrimidinone (2.78 mL), and the mixture was stirred at -78°C for 3 h. oo 15 The reaction was warmed to 25°C and was stirred at 25°C for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride . solution (25 mL) and was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organics were washed with a saturated aqueous lithium chloride solution (2 x 25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (1.63 g, 46.8%) as pale yellow oil: EI-HRMS m/e calcd for C;sH9NO,4 (M™) 277.1314, found 277.1317.
A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (0.55 g, 2.0 mmol) in tetrahydrofuran/water (10 mL, 3:1) was treated with lithium hydroxide (185 mg, 4.40 mmol). The reaction was stirred at 25°C for 48 h. The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (25 mL) and extracted with ether - (1 x 20 mL). The aqueous layer was acidified to pH = 2 with a 3N aqueous hydrochloric
- Te acid solution. The product was extracted into methylene chloride (3 x 25 mL), washed with a saturated aqueous sodium chloride solution (2 x 25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 3-cyclopentyl-2-(3-nitro-phenyl)-propionic oo acid (0.48 g, 91.9%) as a tan solid: mp 95-99°C; EIF-HRMS m/e calcd for CiaH17NO4 (M")263.1157, found 263.1156.
A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid (432 mg, 1.64 mmol) in methylene chloride (16 mL) was cooled to 0°C and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.90 mL, 1.80 mmol) and a few drops of N,VN- dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 1.2 h. The reaction mixture was then treated with a solution of 2-aminothiazole (361.4 mg, 3.61 mmol) in tetrahydrofuran (16 mL) and N,N-diisopropylethylamine (0.70 mL, 3.93 mmol). The reaction mixture was stirred at 25°C for 6 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-yl- propionamide (409.3 mg, 72.2%) as a tan solid: mp 171-174°C; EI-HRMS m/e calcd for
C17H1oN505S (M™) 345.1147, found 345.1153.
A solution of 3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-yl-propionamide (327.8 mg, 0.95 mmol) in ethyl acetate (25 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under hydrogen gas at 60 psi at 25°C for 3 h. The catalyst i ) was then filtered off through a pad of celite (ethyl acetate). The filtrate was concentrated in vacuo to give 2-(3-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (310 mg, 100%) as a white solid: mp 158-160°C; EI-HRMS m/e calcd for C;7H;1N30S (M") 315.1405, found 315.1405.

Claims (32)

  1. R* is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl, -(CH2),-C(O)OR® or -C(0)-(CH2),-C(O)OR’; R’ is hydrogen, lower alkyl or perfluoro-lower alkyl; R® R’ and R® are independently hydrogen or lower alkyl; and 3 nis0,1,2,3 or4; © or apharmaceutically acceptable salt thereof. oo
  2. 2. A compound according to claim 1, wherein R' and R? are independently hydrogen, halo, amino, hydroxyamino, cyano, nitro, lower alkyl, OR’, -C(O)OR’, perfluoro-lower alkyl, lower alkyl thio, perfluoro- lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or sulfonamido; R’ is cycloalkyl having from 3 to 7 carbon atoms; R* is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring ; 15 connected by a ring carbon atom to the amine group shown, which five- or six- membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, -(CH,),-OR®, -(CH,),-C(O)OR’, -(CH,),-C(O)NHR®, -C(O)-C(O)OR® or -(CH,),-NHR®; : nis0,1,2,3or4; : R’ is hydrogen, lower alkyl, or perfluoro-lower alkyl; and R® R’ and R® are independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof.
    _— esse
  3. 3. A compound according to any of claims 1 to 2, wherein R* is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring selected from the group consisting of thiazolyl, pyridinyl. imidazolyl, isoxazolyl, oxazolyl, pyridazinyl, pynimidinyl or thiadiazolyl.
  4. 4. A compound according to any of claims 1 to 3. wherein R* is unsubstituted thiazolyl, unsubstituted pyridinyl or pyridinyl substituted by halogen, lower alkyl, hydroxy lower alkyl or -C(O)OR’®, wherein R° is lower alkyl.
  5. 5. A compound according to claim 1, wherein R' and R? are independently hydrogen. halo, amino, nitro, cyano, sulfonamido, lower alkyl, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl; R’ is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms; . . __RUs-CONHRY;, R* is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl, ~(CH2)n-C(O)OR? or -C(O)-(CH,),-C(O)OR?; 1 R® and R® are hydrogen or lower alkyl; and nis0,1,2,30r4, or a pharmaceutically acceptable salt thereof.
  6. 6. A compound according to any of claims 1 or 5, wherein R* is -C(O)NHR™, and R* is lower alkyl or lower alkenyl.
  7. 7. A compound according to any of claims 1 to 6, wherein R! is hydrogen, halo, nitro or cyano.
  8. 8. A compound according to any of claims 1 to 7, wherein R! is hydrogen or halo. 0 i
  9. 9. A compound according to any of claims 1 to 8, wherein R? is hydrogen, lower alkyl sulfonyl, perfluoro-lower alkyl, perfluoro-lower alkyl sulfonyl, halo or -OR® wherein R’ is perfluoro-lower alkyl.
  10. 10. A compound according to any of claims 1 to 9, wherein R’ is halo or lower alkyl sulfonyl. oo Se oo
  11. 11. A compound according to any of claims 1 to 10, wherein the amide is in the R configuration at the asymmetric carbon shown.
  12. 12. A compound according to any of claims 1 to 11, wherein R’ is cyclopentyl, cyclohexyl or cycloheptyl. 3 15
  13. 13. A compound according to any of claims 1 t012, wherein R’ is cyclopentyl.
  14. 14. A compound according to any of claims 1 to 13, selected from the group consisting of: 5 2-(3-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(4-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide, 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-vl-propionamide, 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide, 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-nitrophenyl)-N-thiazol-2-yl-propionamide, 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(3-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(4-cyano-phenyl)-3-cyclopentyi-N-thiazol-2-yl-propionamide,
    EE —————— TE —————— 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide, 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-
    propionamide,
    } 5 3-cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide, 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-
    propionamide, 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide, 2-(3.4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide, :
    2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-[4-(propane-1-sulfonyl)-phenyl]-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-
    propionamide,
    7 T2(R)-(3-chloro-4-methanesuifonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl- TT propionamide, 2-[3-chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide, 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide, 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propionamide,
    3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide,
    “ ~3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide,
    3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide, 4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl}-benzoic acid methyl ester,
    - 3-cyclopentyi-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide,
    i -339- 3-cyclopentyl-2-(3-fluoro-4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydrox ymethyl-thiazol-2-yl)- propionamide, 3-cyclopentyl-2-(3.4-dichlorophenyl)-N-[4-(2-hydroxyethyl)-thiazol-2-yl}- propionamide, 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)- — —— propionamide, —_ SE 3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)- propionamide, 3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl}-2-(4-methanesulfonyl-phenyl)- propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methyl-thiazol-2-yl)-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-thiazol-2-yl)-propionamide, { 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl }-acetic acid
    . ethyl ester,
    . {2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl }-acetic acid ) methyl ester, :
    . 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino}-thiazole-4-carboxylic acid methyl ester, : 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester, : ) {2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino}-thiazol-4-yl }-acetic acid ethyl ester, 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester, 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester, {2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino}-thiazol-4-yl}-acetic acid methyl ester, {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl } -acetic acid, { 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino}-thiazol-4-yl }-acetic acid ethyl ester, 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid,
    -_ 34 = 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylic acid, {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino}-thiazol-4-yl } -acetic acid methy] ester. (2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4- carboxylic acid methyl ester, . oo - 2-[3-cyclopentyl-2-(3.4-dichlorophenyl)-propionylamino}-thiazole-5-carboxylic ’ acid methyl ester, 2-[3-cyclopentyl-2-(3.4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester, {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino}-thiazol-4-yl } -acetic acid ethyl ester. {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl } -acetic acid methyl ester, 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methy! ester, ’ 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester, {2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl } -acetic acid methyl ester, 7° 77 7 2:[24(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ER methyl ester, {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4- carboxylic acid ethyl ester, {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-4- acetic acid methyl ester, {2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)- propionylamino}-thiazol-4-yl }-acetic acid methyl ester, EE 2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionylamino]- : thiazole-4-carboxylic acid methyl ester, {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino}-thiazol-4-yl } -oxo-acetic acid ethyl ester, { 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]thiazol-5-yl }-oxo-acetic ethyl ester, {2-[3-cyclopentyl-2-(4-fluoro-3-triflucromethyl-phenyl)-propionylamino]-thiazol- 4-yl}-oxo-acetic acid ethyl ester, {2-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-thiazol- 4-yl}-oxo-acetic acid ethyl ester,
    3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitro-thiazol-2-yl)-propionamide, 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide, 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-2-propionamide, 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide, 2-(3-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
    __ __.. 2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide. ~~ _ _ 2-(4- cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide. 2-(4-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide,
    2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide, 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide, 2-(4-cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide, 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide, 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide,
    = 15 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide,
    i} 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide,
    2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-
    propionamide, 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-
    — 20 propionamide, 3-cyclopentyl-2-(4-ethanesulfonyvl-phenyl)-N-pyridin-2-yl-propionamide, 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide, 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-
    propionamide,
    3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2-yl-
    propionamide, 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carbox ymethylpyridin)-2-yl- propionamide,
    6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester,
    6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid, 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino}-nicotinic acid methyl ester, 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester,
    a __342- o_o 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester, 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester, 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino}-nicotinic acid, 6-[2-(4-cyano-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid, 6-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nicotinic - acid methyl ester, - -- : 6-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nicotinic acid, 6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino}-nicotinic acid methyl ester, 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)- propionamide, 3-cyclopentyl-2-(3.4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propionamide, 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)- propionamide, 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl)- propionamide, N-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-brompyridin)-2-yl-propionamide, 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-yl)- 0 propionamide, N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide, N-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)- propionamide, N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)- propionamide, i N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)- propionamide, 2-(3-bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl- propionamide, N-(5- bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- propionamide, 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl-pyridin- 2-yl)-propionamide, N-(5-chloro-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- propionamide,
    3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-nitropyridin)-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-methylpyridin)-2-yl-propionamide, 3-cyclopentyl-2-(3.4-dichloro-phenyl)-N-(4-methylpyridin)-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(6-methylpyridin)-2-yl-propionamide, 3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoromethanesulfonyl-phenyl)- N propionamide, 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-methyl-pynidin-2-yl)- -—_______ propionamige, ~~ T= : 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide, 3-cvclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide, 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide, g 15 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-6-yl-propionamide, 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyrimidin-4-yl-propionamide, Fa 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide, ) 2-[4-methanesulfonyl phenyl}-3-cyclohexyl N-thiazol-2-yl-propionamide, and a 2-[4-methanesulfonyl phenyl]-3-cycloheptyl N-thiazol-2-yl-propionamide.
    wo
  15. 15. A compound according to any of claims 1 to 13, selected from the group consisting of: 1-(3-cyclopentyl-2-phenyl-propionyl)-3-methyl-urea, 1-[2-(3-chloro-phenyl)-3 cyclopentyl-propionyl]-3-methyl-urea, 1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea, 1-[2-(4-cyano-phenyl)-3-cyclopentyl-propionyl}-3-methyl-urea, 1-[2-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-3-methyl urea, [3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]j-urea, 1-{3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea, 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl}-3-ethyl-urea, 1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-urea, 1-allyl-3-[3-cyclopentyl-2(R)-(3, 4-dichloro-phenyl)-proprionyl}-urea, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea,
    _ 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl}-3-methyl-urea, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-isopropyl-urea, : 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-propyl-urea, 1-[3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionyl}-3-methyl-urea, 3 1-[2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea, : 1-[3-cyclopentyl-2-(4-nitro-phenyl)-propionyl]}-3-methyl-urea, 1-[3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(3-triflucromethanesulfonyl-phenyl)-propionyl]-3-methyl urea, ) 1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl]-3-methyl urea, 1-{2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-proprionyl }-3-methyl-urea, 1-[3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-proprionyl}-3-methyl-urea, 1-[2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea, 1-[2-(3-bromo-4-methanesulfonyi-phenyl)-3-cyclopentyl-proprionyl]-3-methyl- _ urea,
    o . 1-[3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-proprionyl}-3-methyl-urea, Cee 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea, 1-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl- urea, - 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-ethyl-urea, 1-[2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea, 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-proprionyl]-3- methyl-urea, 1-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionyl}-3-methy! urea, ) 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionyl]-3-methyl-urea, [2-(4-chloro-phenyl)-4-methyl-pentanoyl]-urea, [3-cyclopropyl-2-(3,4-dichloro-phenyl)-propionyl}-urea, [3-cyclobutyl-2-(3,4-dichloro-phenyl)-propionyl]-urea, R-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]-urea, 1-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]-3-methyl-urea, 1-[2-(3,4-dichloro-phenyl)-hexanoyl]-3-methyl-urea,
    3-{cyclohexyl-2-(3,4-dichloro-phenyl)-propionyl]-urea, [3-cyclohexyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea, [3-cycloheptyl-2-(3,4-dichloro-phenyl)-propionyl]-urea, 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]}-ureido } -propionic acid ethyl ester, {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido } -acetic acid ethyl ester, 777 {3-[3=cyclopentyl-2-(3;4-dichloro-phenyl)-propionyt]-ureidoj-acetic acid methyl ~~ ester, 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl}-ureido }-propionic acid methyl ester, {3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]j-ureido} -acetic acid ethyl ester, 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl}-ureido } -3-oxo-propionic acid ethyl ester, - 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydrox y-ethyl)-urea, i 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydrox y-propyl)-urea, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydroxy-propyl)-urea, 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydroxy-propyl)-urea, 1-(2-chloro-ethyl)-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-urea, and ’ 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydroxy-propyl)-urea.
  16. 16. A compound according to any of claims 1 to 14, selected from the group consisting of: 3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide, 3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide, 3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide, 3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide, 6-[3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester, N-(5-Chloro-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide, 3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide, 3-Cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoromethanesulfonyl-phenyl)- propionamide, 3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl) propionamide,
    \ : . ~ nnn. < 34 em 6-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino}-nicotinic acid methyl ester, 3-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pynidin-2-yl-propionamide, 3-Cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide, ~ 2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl- propionamide, 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl- propionamide, 2-(4-Chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide, : 10 2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl- + propionamide, © N-(5-Bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- - propionamide, 2-[3-Chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-
    + propionamide, (2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide, 2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl- :
    } propionamide, 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide, Co 220 3-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide, - EE 3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yi- propionamide, and . N-(5-Bromo-pyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3- cyclopentyl-propionamide.
    . . } PCT/EP00/02450
  17. 17. A compound according to any of claims 1 to 13 and 13, selected from the group consisting of: — ——I=[3=cyclopentyl=2(R)=(3;4-dichloro-phenyl)-propionyl]-3-ethyl-urea, - EE 3 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea, 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl urea, 1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl]-3-methyl urea, 1-Allyl-3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-urea, 1-[2-(3-Chioro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl}-3-methyl-urea, 1-[2(R)-(3-Chloro<4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]}-3-methyl- ) urea, and oo 1-[2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl}-3-methyl-urea.
  18. 18. The use of the compounds according to any of claims 1 to 17 for the treatment of type II diabetes.
  19. 19. A pharmaceutical composition comprising a compound of any of claims 1 to 17 and 2 pharmaceutcally acceptable carrier and/or adjuvant.
  20. 20. The use of a compound according to any of claims 1 to 17 for the preparation of medicaments containing a compound according to any of claims 1 to 17 for the treatment or prophylaxis of type II diabetes.
  21. 21. A method for the prophylactic treatment of type II diabetes, which method comprises administering a compound of any of claims 1 to 17 to a human being or an animal.
  22. 22. A process for the preparation of the compounds of formula I according to any of claims 1 : to 17, which process comprises: AMENDED SHEET
    (a) The condensation of a compound of formula XI: R3 i COOH } Xl ’? - 696969696969. oo _ - Rr" _ _ _ ce. - -__ ee wherein R', R* and R® are as defined in claim 1; oo with a compound of the formula VIII: 42 : 3 R™-NH, vil wherein R* is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom - 10 being nitrogen which is adjacent to the connecung rng carbon ‘atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, -(CHz)s-OR®, ~(CH1)a-C(O)OR’, ~(CHa)o-C(O)NHR®, -C(0)-C(O)OR® 13 or -(CH,),-NHR®: RS, R’. R® and n are as defined in claim 1; via peptide coupling to produce a compound of formula I-d:
    R . - Nige i" o I-d R' where R!, R? R’® and R* are as defined above; : optionally followed by the conversion of one or both of the substituents R! and/or R? into another substituent R! and/or R? as defined in claim 1. CLEAN COPY
    3 ~ B
    (b) The reaction of a compound of formula IX: = : NH 2 IX . 2 0 _ - LE a wherein R', R> and R are as defined in claim 1: with a compound of the formula X: R*-N=C=0 X wherein R*! is lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl or -(CHa),-C(O)OR’, wherein R’ is hydrogen or lower alkyl and n is as } defined above; to produce a compound of formula I-a: : } Rr H H . N NJ 41 ’ YR a =%
    wherein R}, R?, R’ and R*! are as defined above; optionally followed by the conversion of one or both of the substituents R' and/or R? into another substituent R! and/or R? as defined in claim 1. 135 (¢) The reaction of a compound of the formula XI: Rr’ OCH : Xi 2 O g' wherein R', R? and R® are as defined in claim 1; CLEAN COPY
    : XN with a compound of the formula: H-NCONH, to produce a compound of the formula I-b: nn NE TE TT — -_ " 3 oo CR 0 O . R' 3 wherein R', R’ and R? are as defined above; optionally followed by the conversion of one or both of the substituents R! and/or R” into another substituent R' and/or R* as defined in claim 1. (d) The reaction of a compound of the formula I-b a y
    N._ NH, hig I-b Rr? 0 0 . R wherein R, R? and R® are as defined in claim 1; with a compound of the formula XIII: : CIC(0)-(CHz)a-C(O)OR® XI wherein R°® is hydrogen or lower alkyl and n is as defined in claim I; to produce a compound of the formula I-c: =¥ N__N GH or® YY a? oO oO © fo) R' wherein R!, R?, R®, R® and n are as defined above; CLEAN COPY
    ° . TT ——rr rr l} 3 A - PCT/EP00/02450 -351- optionally followed by the conversion of one or both of the substituents R' and/or R? into another substituent R' and/or R? as defined in claim 1.
  23. 23. A substance or composition for use in a method for the prophylactic or therapeutic treatment ~~ _oftypell diabetes, said substance or.composition comprising.a compound of any of claims. =~ ___ to 17, and said method comprising administering said substance or composition to a human being or an animal. ’
  24. 24. A compound as claimed in claim 1, substantially as herein described and illustrated.
  25. 25. Use as claimed in claim 18, substantially as herein described and illustrated.
  26. 26. A composition as claimed in claim 19, substantially as herein described and illustrated.
  27. 27. Use as claimed in claim 20, substantially as herein described and illustrated.
  28. 28. A substance or composition for use in a method of treatment as claimed in claim 23, substantially as herein described and illustrated.
  29. 29. A method as claimed in claim 21, substantially as herein described and illustrated.
  30. 30. A process as claimed in claim 22, substantially as herein described and illustrated.
  31. 31. A new compound, a new use of a compound as defined in any one of claims 1 to 17, a substance or composition for a new use in a method of treatment, a new non-therapeutic method of treatment, or a new process for preparing a compound, substantially as herein described.
  32. 32. The invention as described hereinbefore. AMENDED SHEET
ZA200107833A 1999-03-29 2001-09-21 Glucokinase activators. ZA200107833B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US12670799P 1999-03-29 1999-03-29

Publications (1)

Publication Number Publication Date
ZA200107833B true ZA200107833B (en) 2002-12-23

Family

ID=27754217

Family Applications (1)

Application Number Title Priority Date Filing Date
ZA200107833A ZA200107833B (en) 1999-03-29 2001-09-21 Glucokinase activators.

Country Status (1)

Country Link
ZA (1) ZA200107833B (en)

Similar Documents

Publication Publication Date Title
RU2242469C2 (en) Glucokinase activating agents
EP1169312B1 (en) Glucokinase activators
KR100502032B1 (en) Trans olefinic glucokinase activators
JP4091600B2 (en) Substituted phenylacetamide and its use as a glucokinase activator
EP1282611B1 (en) Substituted phenylacetamides and their use as glucokinase activators
US6320050B1 (en) Heteroaromatic glucokinase activators
US6610846B1 (en) Heteroaromatic glucokinase activators
ZA200107833B (en) Glucokinase activators.