HK1204286B - Ghrelin receptor agonists for the treatment of achlorhydria - Google Patents
Ghrelin receptor agonists for the treatment of achlorhydriaInfo
- Publication number
- HK1204286B HK1204286B HK15104901.3A HK15104901A HK1204286B HK 1204286 B HK1204286 B HK 1204286B HK 15104901 A HK15104901 A HK 15104901A HK 1204286 B HK1204286 B HK 1204286B
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- Prior art keywords
- alkyl
- oxo
- amino
- group
- ethyl
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Description
Technical Field
The present invention relates to the provision of a medicament for increasing gastric acid secretion. In detail, the present invention relates to the use of a compound having agonistic activity to ghrelin receptor or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of diseases including achlorhydria associated with abnormal secretion of gastric acid. The invention relates to the use of the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or salt together with one or more of any of the 2 nd active agents.
The present invention relates to a method of treating diseases including achlorhydria associated with abnormal secretion of gastric acid by administering a compound of the present invention or a composition comprising the same to a human or animal.
Background
The invention also relates to pharmaceutical compositions or kits comprising a compound of the invention or a pharmaceutically acceptable salt thereof for use in the treatment of said diseases.
Digestive tract diseases are among the common diseases in routine clinical practice.
In order to treat diseases involving excessive gastric acid secretion, gastric acid secretion inhibitors (aluminum hydroxide xerogels, magnesium oxide, etc.), anti-digestive drugs (sucralfate, ecabet sodium, etc.), gastric acid secretion inhibitors (anticholinergic drugs, H2 blockers, proton pump inhibitors, etc.), and the like are clinically used. The development of H2 blockers and proton pump inhibitors has made breakthrough progress in the treatment of upper gastrointestinal diseases.
On the other hand, preferred drugs for the treatment of diseases such as achlorhydria involving low or no gastric acid secretion have not been provided. Therefore, as an agent for promoting gastric acid or gastric secretion, 1) aromatic bitters such as swertia herb, quassia and phellodendron; 2) fragrances, such as anise, cinnamon; 3) digestive juices or enzymes (digestive fluids or enzymes), such as amylase, pepsin, amylase and lipase; 4) an acetylcholine derivative; and 5) acids such as hydrochloric acid, citric acid and tartaric acid.
It is known that the proportion of achlorhydria patients with a pH > 5.5 in the stomach increases with age, over 60% in the 50-year-old population (Journal of pharmacological, vol 7,656-664, 1984).
As described above, for gastric ulcer, duodenal ulcer and other peptic ulcers, drugs that inhibit digestive juices and other intestinal wall infiltration factors (e.g., gastric acid secretion blockers and antacids) and drugs that enhance defense mechanisms (e.g., mucosa protectors) are used. Although promoting gastric acid secretion is effective for patients with chronic gastritis, particularly atrophic gastritis, in the present situation, no gastric motility promoting drug has been developed which is pharmacologically suitable for human or animal.
In addition, achlorhydria is observed in patients with anemia symptoms. Iron deficiency anemia is a long-term side effect of gastric bypass surgery, a recognition that accounts for the importance of gastric acid in dietary iron absorption (Suzana Kovaca, Gregory J. Anderson b, Graham S. Baldwin, Biochimica et Biophysica Acta, Molecular Cell Research, Volume 1813, Issue 5, 889-containing 895, May 2011).
It is also believed that gastric acid secretion plays a very important role in calcium absorption because both dissociation of food-calcium complexes and dissolution of calcium salts are highly dependent on The pH of The acid (Bo-Linn GW, Davis GR, Buddrus DJ, Morawski SG, Santa Ana C and Fordran JS, J.Clin.Invest.,73:640-647, 1984; Nordin, B.E.C., gastroenterology.54:294-301, 1968; Ivanovich, P.H.Fellows, and C.Rich, The adsorption of calcium carbonate.Ann.Med.66: 917-923, 1967).
The performance of gastrectomy not only results in decreased production of gastric acid, but can also cause other physiological changes, including effects on calcium absorption including impaired vitamin D absorption and lack of calcitonin synthesis (Gertner J.M., Lilburn M., Domenec M., Br.Med.J.,1, 1310-1312, 1977; Filipponin P., Grego F., Cristallini S.et al, partial stimulation and mineralmethylolism: effects on gastrin-calcein release, Bone Miner.,11, 199-208, 1990).
In addition, Proton Pump Inhibitors (PPIs) are mainly used for the treatment of gastroesophageal reflux disease. Proton pump inhibitor-induced achlorhydria leads to an increase in circulating gastrin and chromogranin a (cga). Chromogranin is a widely used biomarker for gut-based neuroendocrine diagnostics and follow-up (Raines d., Chester m., diebolda.e., mamikune p., Anthony c.t., mamikune g., Woltering e.a., pancreas, May; 41(4): 508-.
In addition to PPIs, achlorhydria is also reported as a side effect of many other drugs. Examples of such drugs include amoxicillin, atorvastatin calcium, calcitriol, carboplatin, clofazimine, cyclosporine, digoxin, esomeprazole magnesium, famotidine, fluconazole, losartan potassium, methotrexate sodium, omeprazole magnesium, pamidronate disodium, pantoprazole sodium, quetiapine fumarate, quinidine gluconate, ranitidine hydrochloride, troglitazone, trovafloxacin mesylate and zoledronic acid.
In light of the above, great efforts have been made to find or prepare compounds against achlorhydria caused by various causes. However, no preferred drug for achlorhydria has been provided so far.
Non-patent documents:
{NPL 1}
Journal of Pharmacobiodynamics,vol 7,656-664,1984
{NPL 2}
Suzana Kovaca,Gregory J.Andersonb,Graham S.Baldwin,Biochimica et Biophysica Acta,Molecular Cell Research,Volume 1813,Issue 5,889-895,May 2011
{NPL 3}
Bo-Linn G.W.,Davis G.R.,Buddrus D.J.,Morawski SG,Santa Ana Cand Fordran JS,J.Clin.Invest.,73:640-647,1984
{NPL 4}
Nordin B.E.C.,Gastroenterology,54:294-301,1968
{NPL 5}
Ivanovich P.,Fellows H.,and Rich C.,The absorption of calciumcarbonate.Ann.Intern.Med.,66:917-923,1967.
{NPL 6}
Gertner J.M.,M.Lilburn,M.Domenec,Br.Med.J.,1,1310-1312,1977
{NPL 7}
Filipponi P.,Gregorio F.,Cristallini S.et al.,Bone Miner.,11,199-208,1990
{NPL 8}
Raines D.,Chester M.,Diebold A.E.,Mamikunian P.,Anthony C.T.,Mamikunian G.,Woltering E.A.,Pancreas.Pancreas.,May；41(4):508-11,2012
disclosure of Invention
In the state of the art mentioned, there is still a need for compounds or compositions that should alleviate or inhibit the progression of achlorhydria.
The present inventors have studied a group of compounds effective in increasing gastric acid secretion, and have concluded that ghrelin receptor agonists enhance gastric acid secretion. Therefore, the ghrelin receptor agonist shown in the working examples of the present invention enhances gastric acid secretion. The gastric acid secretion-improving effect means that it is effective for diseases involving low or no gastric acid secretion.
Many ghrelin receptor agonists have been reported, but the effect of increasing gastric acid secretion has not been clearly demonstrated by those skilled in the art, and thus, according to the present invention, it has been clearly demonstrated that ghrelin receptor agonists enhance gastric acid secretion and are effective in alleviating and preventing various symptoms and diseases accompanied by low or no gastric acid secretion.
The compounds according to the present invention for preventing or treating diseases involving low or no gastric acid secretion include known compounds having ghrelin receptor agonistic activity, and include the compounds having ghrelin receptor agonistic activity disclosed later.
Examples of known compounds having ghrelin receptor agonistic activity are as follows:
compounds represented by capromorelin disclosed in WO 97/024369: 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide and 2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
compounds represented by anarelin disclosed in WO99/58501 and WO 2001/034593: 2-amino-N- [ (1R) -2- [ (3R) -3-benzyl-3- (N, N' -trimethylhydrazinocarbonyl) piperidin-1-yl ] -1- (1H-indol-3-ylmethyl) -2-oxoethyl ] -2-methylpropanamide, also known as: 2-amino-N- ((R) -1- ((R) -3-benzyl-3- (1,2, 2-trimethylhydrazinocarbonyl) piperidin-1-yl) -3- (1H-indol-3-yl) -1-oxopropan-2-yl) -2-methylpropanamide;
the compound disclosed in WO2000/001726 and represented by ST-1141, also known as RC-1141: (E) -N- ((R) -3- ([1,1' -biphenyl ] -4-yl) -1- (((R) -1- (4-hydroxypiperidin-1-yl) -1-oxo-3-phenylpropan-2-yl) (methyl) amino) -1-oxopropan-2-yl) -4- (1-aminocyclobutyl) -N-methylbut-2-enamide;
compounds disclosed in WO2001/096300 and represented by mexirelin: 2-amino-N- ((R) -1- (((R) -1-carboxamido-2- (1H-indol-3-yl) ethyl) amino) -3- (1H-indol-3-yl) -1-oxopropan-2-yl) -2-methylpropanamide;
compounds disclosed in WO2006/009674 and WO2011/041369 and represented by ulimorelin: (2R,5S,8R,11R) -5-cyclopropyl-11- (4-fluorobenzyl) -2,7, 8-trimethyl-4, 5,7,8,10,11,13,14,15, 16-decahydro-2H-benzo [ q ] [1,4,7,10,13] oxazol tetraazacyclooctadiene-6, 9,12(3H) -trione;
compounds represented by ipamorelin disclosed in WO 95/17423: (S) -6-amino-2- ((R) -2- ((R) -2- ((S) -2- (2-amino-2-methylpropanamido) -3- (1H-imidazol-5-yl) propanamido) -3- (naphthalen-2-yl) propanamido) -3-phenylpropanamide, and the like.
The compounds described in the cited documents are all compounds described in the cited claims. In addition, the above-mentioned citations are incorporated in the content of the present specification.
When administered orally, the molecular weight of the compound of the present invention is preferably less than 800 in view of gastrointestinal absorption.
Especially preferred are capromorelin, 2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide; anarelin, ST-1141, maxirelin, ulimorelin, ipamorelin. The compounds of the present invention include solvates, complexes, polymorphs, prodrugs, isomers and isotopically labeled compounds thereof described later.
The key points of the invention are as follows:
[1] use of one or more substances selected from the group consisting of a compound of formula (I), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically acceptable salt thereof, and a prodrug, which can be abbreviated as a compound of the present invention, for the preparation of a medicament for the treatment of achlorhydria in a human or an animal:
{ chemical formula 1}
In the above formula:
e is 0 or 1;
n and w are each independently 0,1 or 2, provided that w and n cannot both be 0;
y is oxygen or sulfur;
R1is hydrogen, -CN, - (CH)2)qN(X6)C(O)X6、-(CH2)qN(X6)C(O)(CH2)t-A1、-(CH2)qN(X6)SO2(CH2)t-A1、-(CH2)qN(X6)SO2X6、-(CH2)qN(X6)C(O)N(X6)(CH2)t-A1、-(CH2)qN(X6)C(O)N(X6)(X6)、-(CH2)qC(O)N(X6)(X6)、-(CH2)qC(O)N(X6)(CH2)t-A1、-(CH2)qC(O)OX6、-(CH2)qC(O)O(CH2)t-A1、-(CH2)qOX6、-(CH2)qOC(O)X6、-(CH2)qOC(O)(CH2)t-A1、-(CH2)qOC(O)N(X6)(CH2)t-A1、-(CH2)qOC(O)N(X6)(X6)、-(CH2)qC(O)X6、-(CH2)qC(O)(CH2)t-A1、-(CH2)qN(X6)C(O)OX6、-(CH2)qN(X6)SO2N(X6)(X6)、-(CH2)qS(O)mX6、-(CH2)qS(O)m(CH2)t-A1、-(C1-C10) Alkyl, - (CH)2)t-A1、-(CH2)q-(C3-C7) Cycloalkyl, - (CH)2)q-Y1-(C1-C6) Alkyl, - (CH)2)q-Y1-(CH2)t-A1Or- (CH)2)q-Y1-(CH2)t-(C3-C7) A cycloalkyl group;
wherein, in R1In the definition of (A), the alkyl and cycloalkyl groups are optionally substituted by (C)1-C4) Alkyl, hydroxy, (C)1-C4) Alkoxy, carboxy, -CONH2、-S(O)m(C1-C6) Alkyl, -CO2(C1-C4) Alkyl esters, 1H-tetrazol-5-yl or 1,2 or 3 fluoro substitutions; y is1Is O, S (O)m、-C(O)NX6-、-CH＝CH-、-C≡C-、-N(X6)C(O)-、-C(O)NX6-、-C(O)O-、-OC(O)N(X6) -or-oc (o) -;
q is 0,1, 2,3 or 4;
t is 0,1, 2 or 3;
m is 0,1 or 2;
said (CH)2)qGroup and (CH)2)tThe radicals may be optionally substituted by hydroxy or (C)1-C4) Alkoxy, carboxy, -CONH2、-S(O)m-(C1-C6) Alkyl, -CO2(C1-C4) Alkyl ester, 1H-tetrazol-5-yl, 1,2 or 3 fluoro, or1 or 2 (C)1-C4) Alkyl substitution;
R2is hydrogen, (C)1-C8) Alkyl, - (C)0-C3) Alkyl radical- (C)3-C8) Cycloalkyl, - (C)1-C4) alkyl-A1Or A1；
Wherein, in R2In the definition of (1), the alkyl and the cycloalkyl are optionally substituted by hydroxy, -C (O) OX6、-C(O)N(X6)(X6)、-N(X6)(X6)、-S(O)m(C1-C6) Alkyl, -C (O) A1、-C(O)(X6)、CF3CN or 1,2 or 3 halogen substitutions;
R3is A1、(C1-C10) Alkyl, - (C)1-C6) alkyl-A1、-(C1-C6) Alkyl radical- (C)3-C7) Cycloalkyl, - (C)1-C5) alkyl-X1-(C1-C5) Alkyl, - (C)1-C5) alkyl-X1-(C0-C5) alkyl-A1Or- (C)1-C5) alkyl-X1-(C1-C5) Alkyl radical- (C)3-C7) A cycloalkyl group;
wherein, in R3In the definition of (1), the alkyl group is optionally substituted by-S (O)m(C1-C6) Alkyl, -C (O) OX31,2,3,4 or 5 halogens, or 1,2 or 3 OX3Substitution;
X1is O, S (O)m、-N(X2)C(O)-、-C(O)N(X2)-、-OC(O)-、-C(O)O-、-CX2＝CX2-、-N(X2)C(O)O-、-OC(O)N(X2) -or-C ≡ C-;
R4is hydrogen, (C)1-C6) Alkyl or (C)3-C7) Cycloalkyl, or, R4And R3And the carbon atoms to which they are bonded form (C5-C7) Cycloalkyl group, (C)5-C7) Cycloalkenyl, partially or fully saturated 4-to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or R4Is a bicyclic ring system consisting of a partially saturated or fully saturated 5-or 6-membered ring fused to a partially saturated, fully unsaturated or fully saturated 5-or 6-membered ring and optionally having 1-4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X4is hydrogen or (C)1-C6) Alkyl, or, X4And R4And with X4A nitrogen atom bound to and R4The bonded carbon atoms together form a 5-7 membered ring;
R6is a key or
{ chemical formula 2}
Wherein a and b are independently 0,1, 2 or 3;
X5and X5aEach independently selected from hydrogen, trifluoromethyl, A1And optionally substituted (C)1-C6) Alkyl groups;
at X5And X5aIn the definition of (1), the optionally substituted (C)1-C6) Alkyl is optionally selected from A1、OX2、-S(O)m(C1-C6) Alkyl, -C (O) OX2、(C3-C7) Cycloalkyl, -N (X)2)(X2) and-C (O) N (X)2)(X2) Substituted with a substituent in the group formed;
the compound contains X5Or X5aWith carbon containing R7And R8Form together 1 or 2 alkylene bridges, wherein each alkyleneThe radical bridge contains from 1 to 5 carbon atoms, with the proviso that when 1 alkylene bridge is formed, X5Or X5aMay be on the carbon atom but not both, and R7Or R8May be on the nitrogen atom but not both, further provided that, when 2 alkylene bridges are formed, X5And X5aCannot be on the carbon atom, and R7And R8Cannot be located on the nitrogen atom; or
X5And X5aAnd together with the carbon atom to which they are bonded form a partially or fully saturated 3-to 7-membered ring, or a partially or fully saturated 4-to 8-membered ring having 1-4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or
X5And X5aAnd the carbon atoms to which they are bonded, together form a bicyclic ring system consisting of a partially saturated or fully saturated 5-or 6-membered ring optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5-or 6-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
Z1is a bond, O or N-X2Provided that when a and b are both 0, Z1Is not N-X2Or O;
R7and R8Independently hydrogen or optionally substituted (C)1-C6) An alkyl group;
wherein, in R7And R8In the definition of (1), the optionally substituted (C)1-C6) Alkyl is independently optionally substituted by A1、-C(O)O-(C1-C6) Alkyl, -S (O)m(C1-C6) Alkyl, 1-5 halogens, 1-3 hydroxyls, 1-3-O-C (O) (C)1-C10) Alkyl or 1-3 (C)1-C6) Alkoxy substitution; or
R7And R8May be taken together to form- (CH)2)r-L-(CH2)r-; wherein L is C (X)2)(X2)、S(O)mOr N (X)2)；
In each case, A1Independently is (C)5-C7) Cycloalkenyl, phenyl or a substituent formed by eliminating a hydrogen atom from a partially saturated, fully saturated or fully unsaturated 4-to 8-membered ring, a bicyclic system consisting of a partially saturated, fully unsaturated or fully saturated 5-or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5-or 6-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
in each case, when A1When they are bicyclic, A1Is optionally substituted in 1 or any 2 rings by 3 or less substituents, each substituent is independently selected from the group consisting of F, Cl, Br, I, OCF3、OCF2H、CF3、CH3、OCH3、-OX6、-C(O)N(X6)(X6)、-C(O)OX6Oxo, and (C)1-C6) Alkyl, nitro, cyano, benzyl, -S (O)m(C1-C6) Alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkoxy, halophenyl, methylenedioxy, -N (X)6)(X6)、-N(X6)C(O)(X6)、-SO2N(X6)(X6)、-N(X6)SO2-phenyl, -N (X)6)SO2X6、-CONX11X12、-SO2NX11X12、-NX6SO2X12、-NX6CONX11X12、-NX6SO2NX11X12、-NX6C(O)X12Imidazolyl, thiazolyl or tetrazolyl, with the proviso that when A1Optionally substituted with methylenedioxy, it may be substituted with only 1 methylenedioxy;
wherein, X11Is hydrogen or optionally substituted (C)1-C6) An alkyl group;
at X11In the definition of (1), the optionally substituted (C)1-C6) Alkyl is independently optionally substituted by phenyl, phenoxy, (C)1-C6) Alkoxycarbonyl, -S (O)m(C1-C6) Alkyl, 1-5 halogens, 1-3 hydroxyls, 1-3 (C)1-C10) Alkanoyloxy or 1-3 (C)1-C6) Alkoxy substitution;
X12is hydrogen, (C)1-C6) Alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, with the proviso that when X12When not hydrogen, X12Optionally 1-3 independently selected from Cl, F, CH3、OCH3、OCF3And CF3Substituted with a substituent in the group formed; or
X11And X12Together form- (CH)2)r-L1-(CH2)r-; wherein L is1Is C (X)2)(X2)、O、S(O)mOr N (X)2)；
In each case, r is independently 1,2, or 3;
in each case, X2Independently hydrogen, optionally substituted (C)1-C6) Alkyl or optionally substituted (C)3-C7) Cycloalkyl, wherein at X2In the definition of (1), the optionally substituted (C)1-C6) Alkyl and optionally substituted (C)3-C7) Cycloalkyl is independently optionally substituted by-S (O)m(C1-C6) Alkyl, -C (O) OX31-5 halogens or 1-3 OX3Substitution;
in each case, X3Independently is halogen or (C)1-C6) An alkyl group;
X6independently hydrogen, optionally substituted (C)1-C6) Alkyl, (C)2-C6) Halogenated alkyl, optionally substituted (C)3-C7) Cycloalkyl group, (C)3-C7) -halogenated cycloalkyl, wherein in X6In the definition of (1), (C) optionally substituted1-C6) Alkyl and optionally substituted (C)3-C7) Cycloalkyl is independently optionally substituted by 1 or 2 (C)1-C4) Alkyl, hydroxy, (C)1-C4) Alkoxy, carboxyl, CONH2、-S(O)m(C1-C6) Alkyl, carboxylic ester group, (C)1-C4) Alkylcarboxy ester or 1H-tetrazol-5-yl substitution; or, when there are 2X's on 1 atom6Group and 2X6Independently is (C)1-C6) When alkyl, said 2 is (C)1-C6) Alkyl optionally bonded to said 2X6The bonded atoms together forming any of oxygen, sulfur, or NX74-to 9-membered ring of (a);
X7is hydrogen or optionally substituted by hydroxy (C)1-C6) An alkyl group; in each case, m is independently 0,1 or 2;
with the following conditions:
X6and X12When using C (O) X6、C(O)X12、SO2X6Or SO2X12Formally linked to C (O) or SO2When it is not hydrogen;
when R is6When it is a bond, L is N (X)2) In- (CH)2)r-L-(CH2)r-each r is independently 2 or 3;
[2] use of one or more substances selected from the group consisting of a compound of formula (II), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 3}
In the above formula:
R1is- (C)1-C3) Alkyl-phenyl, - (C)1-C3) Alkyl-pyridyl, - (C)1-C3) Alkyl-quinolyl or- (C)1-C3) Alkyl-thiazolyl, wherein, the R1Wherein the phenyl group is optionally substituted by 1 or 2 groups selected from the group consisting of halo, CF3、CH3And phenyl is substituted with a substituent in the group consisting of;
R2is- (C)1-C4) Alkyl or- (C)1-C4) alkyl-CF3；
R3Is- (C)1-C4) Alkyl indolyl, - (C)1-C4) Alkyl phenyl, - (C)1-C4) alkyl-O- (C)1-C4) alkyl-Ar, - (C)1-C4) alkyl-S- (C)1-C4) alkyl-Ar, wherein Ar is phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl or benzisoxazolyl, and the Ar is optionally substituted by 1 or 2 groups selected from halogen and OCF3、CF3And CH3Substituted with a substituent in the group formed; and is
R6is-C (X)5)(X5) Wherein X is5Is- (C)1-C6) An alkyl group;
[3] the use according to [1] or [2], wherein the compound is selected from the group consisting of:
2-amino-N- [1- (3a- (R, S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridine-5-carbonyl) -4-phenyl (R) -butyl ] isobutyramide;
2-amino-N- [1- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridine-5-carbonyl) -4-phenyl (R) -butyl ] isobutyramide;
2-amino-N- [1- (3a- (S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridine-5-carbonyl) -4-phenyl (R) -butyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-3-oxo-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-3-oxo-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydro-pyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-3-oxo-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (3a- (R, S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (3a- (R) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (3a- (S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-tert-butyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-tert-butyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-tert-butyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3 a- (R) -pyridin-2-ylmethyl-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3 a- (S) -pyridin-2-ylmethyl-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (3-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (3-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (3-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-dichloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-dichloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-dichloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-thiophen-2-ylmethoxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,5, 7-hexahydropyrazolo [3,4-c ] pyridin-6-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-thiophen-2-ylmethoxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,5, 7-hexahydropyrazolo [3,4-c ] pyridin-6-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-thiophen-2-ylmethoxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,5, 7-hexahydropyrazolo [3,4-c ] pyridin-6-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (3, 4-difluoro-benzyloxymethyl) -2-oxo-ethyl ] -2-methyl-propionamide;
2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (3, 4-difluoro-benzyloxymethyl) -2-oxo-ethyl ] -2-methyl-propionamide;
2-amino-N- [2- (3a- (S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (3, 4-difluoro-benzyloxymethyl) -2-oxo-ethyl ] -2-methyl-propionamide; and
a pharmaceutically acceptable salt thereof;
[4] the use according to any one of [1] to [3], wherein the compound is selected from the group consisting of:
2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide; and
a pharmaceutically acceptable salt thereof;
[5] use of one or more substances selected from the group consisting of a compound of formula (III), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 4}
In the above formula:
R1is hydrogen or C optionally substituted by more than 1 aryl or heteroaryl1-6-an alkyl group;
a and d are each independently 0,1, 2 or 3;
b and c are each independently 0,1, 2,3,4 or 5, provided that b + c is 3,4 or 5;
d is R2-NH-(CR3R4)e-(CH2)f-M-(CHR5)g-(CH2)h-，
Wherein R is2、R3、R4And R5Independently hydrogen, or C optionally substituted with 1 or more halogen, amino, hydroxy, aryl or heteroaryl1-6-an alkyl group; or
R2And R3Or R2And R4Or R3And R4Can form- (CH) at will2)i-U-(CH2)j-，
Wherein i and j are independently 1 or 2, U is-O-, -S-or a bond;
h and f are independently 0,1, 2 or 3;
g and e are independently 0 or 1;
m is a bond, -CR6＝CR7-, arylene, heteroarylene, -O-or-S-;
R6and R7Independently hydrogen, or C optionally substituted by 1 or more aryl or heteroaryl groups1-6-an alkyl group;
g is-O- (CH)2)k-R8、
{ chemical formula 5}
J is-O- (CH)2)lR13、
{ chemical formula 6}
Wherein R is8、R9、R10、R11、R12、R13、R14、R15、R16And R17Each independently is hydrogen, halogen, aryl, heteroaryl, C1-6-alkyl or C1-6-an alkoxy group;
k and l are independently 0,1 or 2;
e is-CONR18R19、-COOR19、-(CH2)m-NR18SO2R20、-(CH2)m-NR18COR20、-(CH2)m-OR19、-(CH2)m-OCOR20、-CH(R18)R19、-(CH2)m-NR18-CS-NR19R21Or- (CH)2)m-NR18-CO-NR19R21(ii) a Or
E is-CONR22NR23R24，
Wherein R is22Is hydrogen or C optionally substituted by more than 1 aryl or heteroaryl1-6-alkyl, or optionally 1 or more C1-6-alkyl-substituted aryl or heteroaryl; r23Is C optionally substituted by 1 or more aryl or heteroaryl groups1-6-alkyl, or C1-7-an acyl group; and, R24Is hydrogen or C optionally substituted by more than 1 aryl or heteroaryl1-6-an alkyl group; or optionally 1 or more C1-6-alkyl-substituted aryl or heteroaryl; or
R22And R23May form, together with the nitrogen atom to which they are bonded, optionally more than 1C1-6-alkyl-, halogen-, amino-, hydroxy-, aryl-or heteroaryl-substituted heterocyclic ring systems; or
R22And R24May form, together with the nitrogen atom to which they are bonded, optionally more than 1C1-6-alkyl-, halogen-, amino-, hydroxy-, aryl-or heteroaryl-substituted heterocyclic ring systems; or
R23And R24May form, together with the nitrogen atom to which they are bonded, optionally more than 1C1-6-alkyl-, halogen-, amino-, hydroxy-, aryl-or heteroaryl-substituted heterocyclic ring systems;
wherein m is 0,1, 2 or 3,
R18、R19and R21Independently hydrogen or optionally halogen, -N (R)25)R26Substituted C1-6-alkyl, wherein R25And R26Independently is hydrogen or C1-6-an alkyl group; hydroxy, C1-6-alkoxy, C1-6Alkoxycarbonyl, C1-6-an alkylcarbonyloxy group or an aryl group; or
R19Is composed of
{ chemical formula 7}
Wherein the content of the first and second substances,
q is-CH < or-N <,
k and L are independently-CH2-、-CO-、-O-、-S-、-NR27-or a bond(s),
wherein R is27Is hydrogen or C1-6-an alkyl group;
n and o are independently 0,1, 2,3 or 4;
R20is C1-6-alkyl, aryl or heteroaryl;
provided that, if M is a bond, E is-CONR22NR23R24；
[6] The use according to [5], which is a compound of the following formula (IV):
{ chemical formula 8}
[7] Use of one or more substances selected from the group consisting of a compound of formula (V), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 9}
In the above formula:
R1is hydrogen or C1-6-an alkyl group;
R2is hydrogen or C1-6-an alkyl group;
l is
{ chemical formula 10}
Wherein R is4Is hydrogen or C1-6-an alkyl group;
p is 0 or 1;
q, s, t, u are each independently 0,1, 2,3 or 4;
r is 0 or 1;
q + r + s + t + u is 0,1, 2,3 or 4;
R9、R10、R11and R12Are each independently hydrogen or C1-6-an alkyl group;
q is > N-R13Or is
{ chemical formula 11}
Wherein o is 0,1 or 2;
t is-N (R)15)(R16) Or a hydroxyl group;
R13、R15and R16Are each independently hydrogen or C1-6-an alkyl group;
R14is hydrogen, aryl or heteroaryl;
g is-O- (CH)2)k-R17、
{ chemical formula 12}
Wherein R is17、R18、R19、R20And R21Each independently is hydrogen, halogen, aryl, heteroaryl, C1-6-alkyl or C1-6-an alkoxy group;
k is 0,1 or 2;
j is-O- (CH)2)lR22、
{ chemical formula 13}
Wherein R is22、R23、R24、R25And R26Each independently is hydrogen, halogen, aryl, heteroaryl, C1-6-alkyl or C1-6-an alkoxy group;
l is 0,1 or 2;
a is 0,1, 2;
b is 0,1, 2;
c is 0,1, 2;
d is 0 or 1;
e is 0,1, 2 or 3;
f is 0 or 1;
R5is hydrogen, or C optionally substituted by 1 or more hydroxy, aryl or heteroaryl groups1-6-an alkyl group;
R6and R7Each independently is hydrogen, or C optionally substituted with 1 or more halogen, amino, hydroxy, aryl or heteroaryl1-6-an alkyl group;
R8is hydrogen or optionally substituted by 1 or more halogen,Amino, hydroxy, aryl or heteroaryl substituted C1-6-an alkyl group;
R8and R7Or R6And R8Or R7And R8Can form- (CH) at will2)i-U-(CH2)j-, wherein i and j are each independently 1,2 or 3, and U is-O-, -S-, or a bond;
m is arylene, heteroarylene, -O-, -S-or-CR27＝CR28-；
R27And R28Each independently is hydrogen or C optionally substituted with 1 or more aryl or heteroaryl1-6-an alkyl group.
[8] The use according to [7], wherein the compound is a compound of the following formula (VI):
{ chemical formula 14}
[9] Use of one or more substances selected from the group consisting of a compound of formula (VII), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 15}
In the above formula:
*represents a carbon atom having R or S configuration when the carbon atom is a chiral carbon atom, R being1And R3One of which is a hydrogen atom and the other is a group of formula (A);
{ chemical formula 16}
R2Is a hydrogen atom, a straight chain or a branched chain C1-C6Alkyl, aryl, heterocyclyl, cycloalkyl, (CH)2)nAryl radicals, (CH)2)n-heterocyclyl (CH)2)nCycloalkyl, methanesulfonyl, benzenesulfonyl, C (O) R8A group or a group of one of formulae (B) to (G);
{ chemical formula 17}
R4Is a hydrogen atom or a straight or branched chain C1-C4-an alkyl group,
R5is a hydrogen atom, a straight chain or a branched chain C1-C4Alkyl, (CH)2)nAryl radicals, (CH)2)n-heterocyclyl (CH)2)n-a cycloalkyl group or an amino group,
R6and R7Each independently being a hydrogen atom or a linear or branched C1-C4-an alkyl group,
R8is straight chain or branched C1-C6-alkyl, R9、R10、R11、R12、R13、R14、R15And R16Each independently being a hydrogen atom or a linear or branched C1-C4-alkyl, m is 0,1 or 2, n is 1 or 2;
[10] the use according to [9], wherein the compound is a compound of the following formula (VIII):
{ chemical formula 18}
[11] Use of one or more substances selected from the group consisting of a compound of formula (IX), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 19}
In the above formula:
R1is hydrogen or the side chain of an amino acid, or, R1And R2Together form a 4-, 5-, 6-, 7-or 8-membered ring optionally containing O, S or N atoms in the ring, wherein the ring is optionally defined as R8Substituted, or, R1And R9Together form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined as R8Substitution;
R2is hydrogen or the side chain of an amino acid, or, R1And R2Together form a 4-, 5-, 6-, 7-or 8-membered ring optionally containing O, S or N atoms in the ring, wherein the ring is optionally defined as R8Substituted, or, R2And R9Together form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined as R8Substitution;
R3is hydrogen or the side chain of an amino acid, or, R3And R4Together form a 3-, 4-, 5-, 6-or 7-membered ring optionally containing an O or S atom in the ring, wherein the ring is optionally substitutedR is defined as8Substituted, or, R3And R7Or R3And R11Together form a 4-, 5-, 6-, 7-or 8-membered heterocyclic ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined by R as defined below8Substitution;
R4is hydrogen or the side chain of an amino acid, or, R3And R4Together form a 3-, 4-, 5-, 6-or 7-membered ring optionally containing an O or S atom in the ring, wherein the ring is optionally defined by R as defined below8Substituted, or, R4And R7Or R4And R11Together form a 4-, 5-, 6-, 7-or 8-membered heterocyclic ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined by R as defined below8Substitution;
R5and R6Each independently hydrogen or the side chain of an amino acid, or, R5And R6Together form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing O, S or N atoms in the ring, wherein the ring is optionally defined as R8Substitution;
R7is hydrogen, C1-C10Alkyl, substituted C1-C10-alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, or, R3And R7Or R4And R7Together form a 4-, 5-, 6-, 7-or 8-membered heterocyclic ring optionally containing O, S or further containing a N atom in the ring, wherein the ring is optionally substituted with R8Substitution;
R8substituted with more than 1 hydrogen atom of the 3-, 4-, 5-, 6-, 7-or 8-membered ring structure and independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, mercapto, sulfinyl, sulfonyl, and the likeAnd sulfonamide group, or R8Is a fused cycloalkyl, substituted fused cycloalkyl, fused heterocyclyl, substituted fused heterocyclyl, fused aryl, substituted fused aryl, fused heteroaryl, or substituted fused heteroaryl group;
x is O, NR9Or N (R)10)2 +；
Wherein R is9Is hydrogen, C1-C10Alkyl, substituted C1-C10-alkyl, sulfonyl, sulfonamide or amidino, R10Is hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, or, R9And R10Together form a 3-, 4-, 5-, 6-or 7-membered ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined by the definition of R8Substitution;
Z1is O or NR11；
Wherein R is11Is hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, or, R3And R11Or R4And R11Together form a 4-, 5-, 6-, 7-or 8-membered heterocyclic ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined by R8Substitution;
Z2is O or NR12,
Wherein R is12Is hydrogen, C1-C10-alkyl or substituted C1-C10-an alkyl group;
m, n and p are each independently 0,1 or 2;
t is a divalent radical of the formula,
-U-(CH2)d-W-Y-Z-(CH2)e-，
wherein d and e are each independently 0,1, 2,34 or 5; y and Z are each optionally present; u is-CR21R22-or-C (═ O) -, and is bonded to X of formula (IX); w, Y and Z are each independently selected from the group consisting of-O-, -NR-23-、-S-、-SO-、-SO2-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NH-、-NH-C(＝O)-、-SO2-NH-、-NH-SO2-、-CR24R25-, CH ═ CH-, -C ≡ C-having Z or E configuration, and the group consisting of the following cyclic structural formulae:
{ chemical formula 20}
Wherein G is1And G2Each independently is a bond, or is selected from the group consisting of-O-, -NR39-、-S-、-SO-、-SO2-、-C(＝O)-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)NH-、-NH-C(＝O)-、-SO2-NH-、-NH-SO2-、-CR40R41-, a bivalent radical of the group consisting of-CH ═ CH-and-C ≡ C-having the configuration Z or E; g1The group closest to U is bonded thereto; wherein any carbon atom not otherwise defined in the ring is optionally substituted with N, with the proviso that the ring cannot contain more than 4N atoms; k1、K2、K3、K4And K5Are each independently O, NR42Or S, wherein R42As defined below;
R21and R22Are each independently hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, or, R21And R22Together form a 3-to 12-membered cyclic ring optionally containing 1 or more heteroatoms selected from the group consisting of O, S and N, wherein the ring is optionally R as defined above8Substitution;
R23、R39and R42Each independently is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroCyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, amidino, sulfonyl or sulfonamido;
R24and R25Are each independently hydrogen, C1-C10Alkyl, substituted C1-C10-alkyl, RAA(wherein, RAAIs a side chain of an amino acid), or, R24And R25Together form a 3-to 12-membered cyclic ring optionally containing 1 or more heteroatoms selected from the group consisting of O, S and N; or, R24And R25One of which is hydroxy, alkoxy, aryloxy, amino, mercapto, carbamoyl, amidino, ureido or guanidine, the other is hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, R24And R25Except where the bonded carbon is also bonded to another heteroatom;
R26、R31、R35and R38Each independently substituted, when present, for 1 or more hydrogen atoms in the indicated ring and independently selected from the group consisting of halogen, trifluoromethyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, cyano, nitro, mercapto, sulfinyl, sulfonyl and sulfonamido;
R27optionally, when present, substituted for 1 or more hydrogen atoms on the indicated ring, each independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidinoUreido, amidino, mercapto, sulfinyl, sulfonyl and sulfonamido groups;
R28、R29、R30、R32、R33、R34、R36and R37Optionally present, wherein the carbon atoms to which they are bonded in the ring do not have a double bond, 2 groups optionally present, wherein if present, they each replace 1 hydrogen present in the ring, or, wherein the carbon atoms to which they are bonded in the ring do not have a double bond, 1 or 2 of the 2 hydrogen atoms in the ring are replaced, wherein each group is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, mercapto, sulfinyl, sulfonyl, sulfonamido and halogen (only in the case of a double bond), and wherein
R40And R41Are each independently hydrogen, C1-C10Alkyl, substituted C1-C10-alkyl, R as defined aboveAAOr, R40And R41Together form a 3-to 12-membered cyclic ring optionally containing 1 or more heteroatoms selected from the group consisting of O, S and N, wherein the ring is optionally R as defined above8Substituted, or, R40And R41One of which is hydroxy, alkoxy, aryloxy, amino, mercapto, carbamoyl, amidino, ureido or guanidino, and the other is hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, R40And R41Except where the bonded carbon is also bonded to another heteroatom;
with the proviso that T is not an amino acid residue, a dipeptide fragment, a tripeptide fragment, or a higher order peptide fragment containing standard amino acids.
[12] The use according to [11], wherein the compound is selected from the compounds of the following formulae (Xa), (Xb) and (Xc).
{ chemical formula 21}
[13] Use of one or more substances selected from the group consisting of a compound of formula (XI), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
A-B-C-D(-E)p(XI)
in the above formula:
p is 0 or 1;
a is hydrogen or R1-(CH2)q-(X)r-(CH2)s-CO-, wherein,
q is 0 or an integer of 1 to 5;
r is 0 or 1;
s is 0 or an integer from 1 to 5;
R1is hydrogen, imidazolyl, guanidino, piperazinyl, morpholinyl, piperidinyl or N (R)2)-R3Wherein R is2And R3Each independently is hydrogen or C optionally substituted with 1 or more hydroxy, pyridyl or furyl groups1-C10-an alkyl group; and is
When r is 1, X is-NH-, -CH2-、-CH＝CH-、
{ chemical formula 22}
Wherein R is16And R17Are each independently hydrogen or C1-C10-an alkyl group;
b is (G)t-(H)uWherein, in the step (A),
t is 0 or 1;
u is 0 or 1;
g and H are amino acid residues selected from the group consisting of natural L-amino acids or their corresponding D-isomers and unnatural amino acids such as 1, 4-diaminobutyric acid, amino-isobutyric acid, 1, 3-diaminopropionic acid, 4-aminophenylalanine, 3-pyridylalanine, 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, 1,2,3, 4-tetrahydronorhalman-3-carboxylic acid, N-methylanthranilic acid, anthranilic acid, N-benzylglycine, 3-amino-3-methylbenzoic acid, 3-amino-3-methylbutyric acid, sarcosine, hexahydronicotinic acid or isohexahydropyronicotinic acid;
when t and u are both 1, the amide bond between G and H is optionally Y-NR18-substituted, wherein Y is-CO-or-CH2-，R18Is hydrogen, C1-C10-alkyl or lower aralkyl;
c is a chemical formula of-NH-CH ((CH)2)w-R4) -a D-amino acid residue of CO-, wherein w is 0,1 or 2; and is
R4Is selected from the group consisting of
{ chemical formula 23}
Optionally halogen, C1-C10Alkyl radical, C1-C10-alkoxy, C1-C10-alkylamino, amino or hydroxy substitution;
when p is 1, D is of the formula-NH-CH ((CH)2)k-R5) D of-CO--an amino acid residue, or, when p is 0, D is-NH-CH ((CH)2)l-R5)-CH2-R6or-NH-CH ((CH)2)m-R5)-CO-R6Wherein, in the step (A),
k is 0,1 or 2;
l is 0,1 or 2;
m is 0,1 or 2;
R5is selected from the group consisting of
{ chemical formula 24}
Each of which is optionally substituted with halogen, alkyl, alkoxyamino or hydroxy; and is
R6Is piperazinyl, morpholinyl, piperidinyl, -OH or-N (R)7)-R8Wherein R is7And R8Are each independently hydrogen or C1-C10-an alkyl group;
when p is 1, E is-NH-CH (R)10)-(CH2)V-R9Wherein v is 0 or an integer of 1 to 8;
R9is hydrogen, imidazolyl, guanidino, piperazinyl, morpholinyl, piperidinyl,
{ chemical formula 25}
(wherein n is 0,1 or 2, R19Is hydrogen or C1-C10-alkyl groups),
{ chemical formula 26}
(wherein o is an integer of 1 to 3), or
N(R11)-R12(wherein, R11And R12Are each independently hydrogen or C1-C10-alkyl) or
{ chemical formula 27}
Optionally substituted with halogen, alkyl, alkoxy, amino, alkylamino, hydroxy, or Amadori (Amadori) rearrangement product of amino and residue formed by elimination of hydrogen from hexopyranose or hexopyranosyl-hexopyranose, respectively;
when p is 1, R10Selected from the group consisting of-H, -COOH, -CH2-R13、-CO-R13or-CH2-OH, wherein,
R13is piperazinyl, morpholinyl, piperidinyl, -OH or-N (R)14)-R15Wherein R is14And R15Are each independently hydrogen or C1-C10-an alkyl group;
the amide bond between B and C, or between A and C when t and u are both 0, is optionally substituted by R18Or Y-NR18-substituted, wherein Y is-CO-or-CH2-，R18Is hydrogen, C1-C10-alkyl or lower aralkyl, or, when p is 1, the amide bond between D and E is optionally substituted by Y-NR18-substituted, wherein Y and R18As defined above;
[14] the use as described in [13], which is a compound of the following chemical formula (XII):
{ chemical formula 28}
[15] The use according to any one of [1] to [14], wherein the molecular weight of the compound is less than 800;
[16] the use according to any one of [1] to [15], wherein the achlorhydria is age-related achlorhydria accompanied by an aging process; chronic gastritis-related achlorhydria; anemic achlorhydria with anemia symptoms; gastric segmental resection-associated achlorhydria; calcium absorption-associated achlorhydria; vitamin D absorption-associated achlorhydria; calcitonin synthesis-related achlorhydria; and drug-induced achlorhydria;
[17] use of a compound as defined in any one of [1] to [15] or a pharmaceutically acceptable salt thereof in combination with one or more 2 nd active agents;
[18] the use according to [17], wherein the 2 nd active agent is selected from any one of the following ingredients:
(i) histamine H2Receptor antagonists, (ii) proton pump inhibitors, (iii) oral antacid mixtures, (iv) mucosal protectants, (v) anti-gastric ulcers, (vi)5-HT3 antagonists, (vii)5-HT4 agonists, (viii) laxatives, (ix) GABAB agonists, (x) GABAB antagonists, (xi) calcium channel blockers, (xii) dopamine antagonists, (xiii) tachykinin (NK) antagonists, (xiv) helicobacter pylori infectives, (xv) nitric oxide synthase inhibitors, (xvi) capsaicin receptor 1 antagonists, (xvii) muscarinic receptor antagonists, (xviii) calmodulin antagonists, (xviii) potassium channel agonists, (xx) beta-1 agonists, (xxbet) alpha agonists, (xxiii) 2 agonists, (xxiv) endothelin A antagonists, (xxv) opioid mu agonists, (xxvi) Opioid μ antagonists, (xxvii) motilin agonists, (xxviii) ghrelin agonists, (xxix) AchE-releasing stimulants, (xxx) CCK-B antagonists, (xxxi) glucagon antagonists, (xxxii)Piperacillin, ampicilin hydrochloride, tetracycline, metronidazole, bismuth citrate and bismuth subsalicylate, (xxxiii) glucagon-like peptide-1 (GLP-1) antagonists, (xxxiv) small conductance calcium activated potassium channel 3(SK-3) antagonists, (xxxv) mGluR5 antagonists, (xxxvi)5-HT3 agonists, (xxxvii) mGluR8 agonists, (xxxviii) chemotherapeutic agents, (xxxix) immunotherapeutic agents, (xL) drugs for cachexia, (xLi) diuretics, and (xLii) antidepressants;
[19] a method of treatment of achlorhydria, which comprises administering an effective amount of a compound as defined in any one of [1] to [15], or a pharmaceutically acceptable salt thereof, to a human or animal;
[20] a pharmaceutical composition for the treatment of achlorhydria comprising a compound as defined in any one of [1] to [15], or a pharmaceutically acceptable salt thereof;
[21] a kit for the treatment of achlorhydria comprising a compound as defined in any one of [1] to [15], or a pharmaceutically acceptable salt thereof;
[22] the kit according to [21], which comprises the compound defined in any one of [1] to [15], or a pharmaceutically acceptable salt thereof, at least one 2 nd active agent, and a container;
[23] a commercial package comprising a pharmaceutical composition comprising a compound as defined in any one of [1] to [15] or a pharmaceutically acceptable salt thereof and a documentation relating to the pharmaceutical composition that indicates that the pharmaceutical composition may or should be used in the treatment of achlorhydria.
According to the formula and the present application, "heteroaryl" may be abbreviated as "hetaryl" and has the meaning indicated if the following terms are not otherwise expressed.
Alkyl groups include alkoxy groups having a length represented in either a straight or a side chain configuration that may optionally contain double or triple bonds. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl, propenyl, butadienyl, hexenyl and the like.
In said definition reference is made to C0-alkyl, when defined, represents a single bond.
The illustrated alkoxy groups include alkoxy groups having a length represented in a straight or side chain configuration that may optionally contain double or triple bonds. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, allyloxy, 2-propynyloxy, isobutenyloxy, hexenyloxy and the like.
The term "halogen" or "halo" includes the halogen atoms fluorine, chlorine, bromine and iodine.
The term "halogenated alkyl" includes alkyl groups as defined above substituted with 1 or more halogen atoms as defined above.
The term "halogenated cycloalkyl" includes cycloalkyl groups as defined above substituted with 1 or more halogen atoms as defined above.
The term "aryl" includes phenyl and naphthyl as well as substituents formed by the elimination of hydrogen from aromatic 5-and 6-membered rings having 1-4 heteroatoms or from fused 5-or 6-membered bicyclic rings having 1-4 heteroatoms of nitrogen, sulfur and/or oxygen. Examples of such heterocyclic aromatic rings are pyridine, thiophene (known as thienyl), furan, benzothiophene, tetrazole, indole, N-methylindole, indoline, indazole, N-formylindole, benzimidazole, thiazole, pyrimidine and thiadiazole.
The term "achlorhydria" as used in this application includes a variety of achlorhydria and is not limited to age-related achlorhydria that accompanies the aging process; chronic gastritis-related achlorhydria; anemic achlorhydria with anemia symptoms; gastric segmental resection-associated achlorhydria; calcium absorption-associated achlorhydria; vitamin D absorption-associated achlorhydria; calcitonin synthesis-related achlorhydria; and drug (e.g., PPI) -induced achlorhydria.
The terms "treated" or "treating" as used herein include reversing, alleviating, inhibiting the progression of, or preventing the disease or condition for which the term is applied. It includes not only the treatment of achlorhydria, but also the alleviation of disorders, the improvement and prevention of QOL. Thus, included are "therapeutic agents" and "prophylactic agents".
One skilled in the art will appreciate that the particular combination of heteroatom containing substituents exemplified herein is to define compounds that are less stable under physiological conditions (e.g., compounds containing acetal, aminal linkages). Therefore, such a compound is not preferable.
Drawings
{ FIG. 1}
Figure 1 shows the effect of vehicle on intragastric pH.
{ FIG. 2}
Figure 2 shows the effect of ghrelin receptor agonist (compound a) on the pH in the stomach. { FIG. 2}
Detailed Description
The present inventors have now sought or prepared compounds which are capable of alleviating achlorhydria and increase gastric acid secretion. As a result of intensive studies, the present inventors have found that a compound having an agonistic activity on a ghrelin receptor sharply decreases the pH value in the stomach and maintains a low value for a long period of time. Thus, the compound of the present invention enhances gastric acid secretion, and provides a promising drug for the treatment of achlorhydria.
Growth hormone releasing peptide receptor agonists have proven to have a variety of pharmacological uses (WhiteH.K., Petrie C.D., LandshulZ W., et Al., J.Clin.Endocrinol.Metab.,94:1198-1206, 2009; Garcia J.M.and Polvion W.J., The Oncoloist, 12:594-600, 2007; Nagaya N., Kojima M., Uematsu M., Yamagishi M., Hosoda H., Oya H., Hayashi Y., and Kangawa K., am.J.Physiol.Regulory.Integged Comp.Physiol.,280: R148-R1487,2001; SmoeteB., Mielsos A, Depor I., thermal I., and P.207, 2009). However, the fact that ghrelin receptor agonists increase gastric acid secretion has not been clarified at all at the present state of the art. Thus, one skilled in the art would not be able to predict the use of ghrelin receptor agonists for achlorhydria.
More than one compound of the invention can be used in effective combination with other pharmacologically active compounds or more than 2 other pharmaceutically active compounds (2 nd active agents).
For example, the ghrelin receptor agonist or a pharmaceutically acceptable salt thereof of the present invention can be administered simultaneously, sequentially or separately with one or more ingredients selected from the group consisting of the following.
(i) Histamine H2Receptor antagonists such as ranitidine, lafutidine, nizatidine, cimetidine, famotidine and roxatidine;
(ii) proton pump blockers such as omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole;
(iii) antacid compounds for oral use, such as Mallox (registered trademark), Aludrox (registered trademark) and Gaviscon (registered trademark);
(iv) mucosa protective agents such as polyprenyl zinc, ecabet sodium, rebamipide, teprenone, cetrimide, sucralfate, copper chlorophyll, and plaunotol;
(v) anti-gastric ulcer agents, such as anti-gastrin vaccines, itramine and Z-360;
(vi)5-HT3antagonists, e.g. dorasx(ii) setron, palonosetron, alosetron, azasetron, ramosetron, mirtazapine, granisetron, tropisetron, E-3620, ondansetron, and indisetron;
(vii)5-HT4agonists such as tegaserod, mosapride, ciniupride and hydroxytryptophan;
(viii) laxatives such as Trifyba (registered trademark), Fybogel (registered trademark), Konsyl (registered trademark), Isogel (registered trademark), Regulan (registered trademark), cellvac (registered trademark), and Normacol (registered trademark);
(ix) GABAB agonists such as baclofen and AZD-3355;
(x) GABAB antagonists, such as GAS-360 and SGS-742;
(xi) Calcium channel blockers such as aranidipine, lacidipine, felodipine, azelnidipine, cilnidipine, lomerizine, diltiazem, granopam, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine, and fasudil;
(xii) Dopamine antagonists such as metoclopramide, domperidone and levosulpiride;
(xiii) Tachykinin (NK) antagonists, in particular NK-3, NK-2 and NK-1 antagonists, such as nepadutant, saredutant, talnetutant, (alpha R,9R) -7- [3, 5-bis (trifluoromethyl) benzyl ] -8,9,10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino (diazocino) [2,1-g ] [1,7] naphthyridine-6, 13-dione (TAK-637), 5- [ [ (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] methyl ] -1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), lansopitant, dapitant, and 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] methylamino ] -2-phenyl-piperidine (2S, 3S);
(xiv) Helicobacter pylori infectious agents, such as clarithromycin, roxithromycin, rotamycin, flurubicin, telithromycin, amoxicillin, ampicillin, temocillin, amoxicillin, sultamicillin, piperacillin, ranicillin, tetracycline, metronidazole, bismuth citrate, and bismuth subsalicylate;
(xv) Nitric oxide synthase inhibitors such as GW-274150, tirargine (tirargine), P54, 1'- (2,2' -disulfanediylbis (ethane-2, 1-diyl)) diguanidine (guanidinoethildifide) and nitroflurbiprofen;
(xvi) Capsaicin receptor 1 antagonists, such as AMG-517 and GW-705498;
(xvii) Muscarinic receptor antagonists such as trospium, solifenacin, tolterodine, tiotropium, cimetium, oxitropium, ipratropium, tiquinium, darifenacin and imidafenacin;
(xviii) Calmodulin antagonists, such as squalamine (squalamine) and DY-9760;
(xix) Potassium channel agonists such as pinadil, tililol, nicorandil, NS-8, and retigabine;
(xx) beta-1 agonists such as dopamine, dienopamine, zamoterol, polycarbobamine and zamoterol;
(xxi) beta-2 agonists such as salbutamol, terbutaline, arformoterol, meluadrine, mabuterol, ritodrine, fenoterol, clenbuterol, formoterol, procaterol, tulobuterol, pirbuterol, bambuterol, tulobuterol, dopexamine and levosalbutamol (levosalbutamol);
(xxii) beta agonists such as isoproterenol and terbutaline;
(xxiii) alpha 2 agonists such as clonidine, medetomidine, lofexidine, moxonidine, tizanidine, guanfacine, guanabenz, talipexole and dexmedetomidine (dexmedetomidine);
(xxiv) Endothelin a antagonists such as bosentan, atrasentan, ambrisentan, clavulan, stasentan, pantosentan and darussian;
(xxv) Opioid μ agonists such as morphine, fentanyl, and loperamide;
(xxvi) Opioid μ antagonists such as naloxone, buprenorphine and alvimopan;
(xxvii) Motilin agonists such as erythromycin, mitoxantrone, SLV-305, and atitemustine (atilmotin);
(xxviii) Ghrelin agonists such as capromorelin and TZP-101;
(xxix) AchE-releasing stimulants such as Z-338 and KW-5092;
(xxx) CCK-B antagonists such as itramine, YF-476, and S-0509;
(xxxi) Glucagon antagonists, such as NN-2501 and A-770077;
(xxxii) Piperacillin, ampicilin hydrochloride, tetracycline, metronidazole, bismuth citrate and bismuth subsalicylate;
(xxxiii) Glucagon-like peptide-1 (GLP-1) antagonists, such as PNU-126814;
(xxxiv) Small-conductance calcium-activated potassium channel 3(SK-3) antagonists such as melimine, dequalinium, atracurium, pancuronium, and tubocurarine;
(xxxv) mGluR5 antagonists, such as ADX-10059 and AFQ-056;
(xxxvi)5-HT3 antagonists, such as promotaxane (pumosetrag: DDP 733);
(xxxvii) mGluR8 agonists, such as (S) -3,4-DCPG and mGluR 8-A;
(xxxviii) Chemotherapeutic agents, such as alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, 5-fluorouracil), antitumor antibiotics (e.g., mitomycin, doxorubicin), plant-derived antitumor drugs (e.g., vincristine, vindesine, paclitaxel), cisplatin, carboplatin, and etoposide; in particular Flutron and Neo-Flutron (which are 5-fluorouracil derivatives);
(xxxix) Immunotherapeutics, such as fungal or bacterial cell wall components (e.g., muramyl dipeptide derivatives, bizuki), immunostimulant polysaccharides (e.g., Balanophora aestivum polysaccharide, schizophyllan, coriolus versicolor polysaccharide), recombinant cytokines (e.g., interferons, Interleukins (IL) and colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin), especially preferably IL-l, IL-2 and IL-12;
(xL) drugs for cachexia, such as cyclooxygenase inhibitors (e.g., indomethacin) [ Cancer research,49, 5935-;
(xLi) diuretics, such as xanthine derivative preparations (e.g., theobromine sodium salicylate and theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentofluthiazide, polythiazide, methyclothiazide), aldosterone antagonist preparations (e.g., spironolactone, triamterene), dehydratase carbonate inhibitors (e.g., acetazolamide), chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mefoside, indole pamide), azoamide, isotridecanol, ethacrynic acid, piretanide, bumetanide, and furosemide; and
(xLii) antidepressants such as citalopram hydrobromide, escitalopram oxalate, fluvoxamine maleate, paroxetine hydrochloride, paroxetine methanesulfonate, sertraline hydrochloride and mirtazapine.
For pharmaceutically acceptable acid addition salts, suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, oxybenzoyl benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, isethionate, methosulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate, gluconate, stearate, succinate, tartrate, tosylate, and trifluoroacetate.
Suitable base addition salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts and zinc salts.
For a review of suitable salts, reference is made to the following: "Handbook of pharmaceutical salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Pharmaceutically acceptable salts of the compounds of the present invention can be readily prepared by suitably mixing a solution of the compound with the desired acid or base. The salt can be collected by filtration if it precipitates from solution, or by evaporating the solvent. The degree of ionization in the salt can be changed from fully ionized to almost non-ionized.
Pharmaceutically acceptable salts of the compounds of the invention include both unsolvated and solvated forms. In the present application, the term "solvate" is used to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g. methanol).
Complexes such as clathrates, drug-host saturated compounds, and the like, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the solvates, are included within the scope of the present invention. In addition, complexes of drugs containing 2 or more organic and/or inorganic components that may be present in stoichiometric or non-stoichiometric amounts are also included in the scope of the present invention. The resulting complex may be ionized, partially ionized or non-ionized. For a review of such complexes, reference is made to the following documents: j Pharm Sd.64(8),1269-1288 by Haleblian (August 1975).
All references to compounds of the invention include references to salts and complexes thereof and references to solvates and complexes of salts thereof.
The compounds of the invention include polymorphs, prodrugs and isomers (including optical isomers, geometric isomers and tautomers) thereof as well as isotopically labeled compounds of the invention as defined herein.
As previously mentioned, the present invention includes all polymorphs as defined above.
So-called "prodrugs" of the compounds of formula (I) are also included within the scope of the present invention. Thus, they themselves have little or no pharmacological activity of specific derivatives of the compounds of formula (I) which, when administered in vivo or on the body surface, are capable of being converted, for example by hydrolytic decomposition, into compounds of formula (I) having the desired activity. Such derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be seen in the following documents: pro-drugs as novelderlivery Systems, Vol.14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press,1987(ed. E BRoche, American Pharmaceutical Association).
Prodrugs based on the invention can be prepared, for example, by reacting suitable functional groups present in compounds of formula (I) as, for example, in the literature: "Pre-existing groups (pro-moieties)" described in Design of drugs by H Bundgaard (Elsevier,1985) were prepared by substituting specific moieties well known to those skilled in the art.
Some examples of prodrugs according to the invention include the following:
(i) when the compounds of the invention contain a carboxylic acid function (-COOH), for example with (C)1-C6) Esters thereof obtained by substituting hydrogen of-COOH with alkanoyloxymethyl;
(ii) when the compound of the present invention contains an alcohol functional group (-OH), for example, (C)1-C6) Ethers thereof obtained by substituting hydrogen of-OH with alkanoyloxymethyl; and
(iii) when the compound of formula (I) contains a primary or secondary amine function (-NH)2or-NHR where R is not H but a substituent), for example, may be used (C)1-C10) Alkanoyl substituted-NH2Or 1 hydrogen or 2 hydrogens in NHR.
Additional examples of substituents based on the examples are known to those skilled in the art and can be found in the references, but are not limited thereto.
Certain compounds of the invention may themselves act as prodrugs of other compounds of the invention.
The compounds of the present invention containing 1 or more asymmetric carbon atoms may exist as 2 or more diastereomers. When the compounds of the present invention contain an alkenyl or alkenylene group, cis/trans (or Z/E) geometric isomers may be achieved. Isomerism (tautomerism) may occur when a compound of the invention contains, for example, a keto group or an oxime group or an aromatic moiety or heteroaromatic ring containing more than 2 nitrogens. Thus a single compound may exhibit more than 1 type of isomerism.
All enantiomers, geometric isomers and tautomeric forms of the invention, including compounds exhibiting more than 1 type of isomerism and mixtures thereof, are included within the scope of the invention. Also included are acid addition salts or base addition salts in which the counterion is optically active, such as D-lactic acid or L-lysine or the racemate (e.g., DL-tartaric acid or DL-arginine).
The cis/trans isomers can be separated by conventional techniques known to those skilled in the art, such as chromatography and fractional crystallization.
Common techniques for preparing or isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, when the compound of formula (I) contains an acidic or basic moiety, with an acid or base, such as tartaric acid or 1-phenylethylamine. The resulting mixture of diastereomers may be separated by chromatography and/or fractional crystallization, or 1 or 2 of the diastereomers may be converted to the corresponding pure enantiomers by methods well known to those skilled in the art.
The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form by using chromatography, typically HPLC, on asymmetric resins based on a mobile layer consisting of a hydrocarbon containing 0-50% isopropanol, typically 2-20%, and 0-5% alkylamine, typically 0.1% diethylamine, typically heptane or hexane. The enriched mixture is provided by concentration of the eluate.
The collection of enantiomers can be isolated by conventional techniques well known to those skilled in the art, for example, by reference to the following references: "Stereochemistry of Organic Compounds" by E LEliel (Wiley, New York, 1994).
The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the present invention in which 1 or more atoms are replaced by atoms having the same atomic order, but a different atomic mass or mass number than what is normally found in nature.
Examples of suitable isotopes that are suitable for inclusion in the compounds of the invention include2H and3h and other hydrogen isotopes,11C、13C and14carbon isotopes such as C,36Chlorine isotopes such as Cl,18F and other fluorine isotopes,123I and125i and other iodine isotopes,13N and15n, etc. nitrogen isotopes,15O、17O and18oxygen isotope such as O,32Phosphorus isotopes such as P, and35s and other sulfur isotopes.
Certain isotopically-labeled compounds of formula (I), for example isotopically-labeled compounds incorporating a radioisotope, are useful in drug and/or matrix tissue distribution studies. From the standpoint of ease of incorporation and rapid detection method, the radioisotope tritium (i.e., tritium)3H) And carbon-14 (i.e.14C) Particularly useful for this purpose.
If substituted with heavier isotopes such as deuterium (i.e. hydrogen2H) The above substitution may be preferred in some cases because of the increased in vivo half-life or reduced dosage requirements, or the like, and the further increased metabolic stability that may provide particular therapeutic advantages.
For example11C、18F、15O and13substitution of positron emitting isotopes such as N may be useful for Positron Emission Tomography (PET) studies for detecting occupancy of a substrate receptor.
The isotopically labeled compound of the present invention can be prepared by a conventional technique known to those skilled in the art, or by a method similar to that described in the examples and preparation section, using an appropriate isotopically labeled reagent in place of a conventionally used non-labeled reagent.
Pharmaceutically acceptable solvates according to the invention include solvates in which the crystallization solvent may be isotopically substituted, for example D2O、d6-acetone, d6-solvates of DMSO.
The compounds of the invention for pharmaceutical use purposes may be administered in crystalline or amorphous product form. These may be obtained, for example, by methods such as precipitation, crystallization, freeze-drying, or spray-drying or evaporative drying, for example, in the form of solid plugs (solid plugs), powders, or films. Microwave or high frequency drying may be utilized for this purpose.
They may be administered alone, or in combination with one or more further compounds of the invention or one or more further drugs (or combinations thereof). Typically, they will be administered in a formulation with more than one pharmaceutically acceptable excipient. The term "excipient" is used for any ingredient other than the compounds of the present invention described in the present application. The choice of excipient will depend on such factors as the particular mode of administration, the effect of the excipient on solubility and stability, and the type of dosage form.
Accordingly, the present invention provides compounds of the present invention, solvates or prodrugs thereof, and compositions comprising a compound selected from one or more pharmaceutically active substances (or a group of compounds that are 2 nd active agents). Also, the present invention provides a pharmaceutical composition comprising such a composition together with a pharmaceutically acceptable additive, diluent or carrier, particularly a pharmaceutical composition for treating various diseases resulting from abnormal gastrointestinal motility. In addition, the present invention provides a kit comprising a 1 st pharmaceutical composition, a 2 nd active agent, and a container, the 1 st pharmaceutical composition containing a compound of the present invention or a pharmaceutically acceptable salt thereof.
A kit comprising a compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of various diseases resulting from abnormal gastrointestinal motility is one of the present invention. Commercial packages contain a pharmaceutical composition containing a compound of the invention or a pharmaceutically acceptable salt thereof and a written matter associated with the pharmaceutical composition (wherein the written matter states that the pharmaceutical composition can or should be used to treat a variety of diseases resulting from abnormal gastrointestinal motility).
The term "treated" as used herein is intended to mean reversing, alleviating, inhibiting the progression of, or preventing a disease or condition for which the term is applied. The term "treatment" as used herein includes not only treatment of diseases caused by abnormal secretion of gastric acid but also alleviation of disorders, improvement of QOL, and so-called prevention concept, and is used in a wide range.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. While particular embodiments of the present invention have been described, other variations and modifications which may be made are part of this invention and are within the scope of the appended claims, as derived from the common general practice in the art, and which depart from this disclosure. The invention also includes equivalents, variations, uses, or adaptations of the invention that come within the spirit of the invention.
The compounds of the present invention are administered in amounts sufficient to ameliorate a variety of disorders resulting from abnormal gastrointestinal motility. The therapeutically effective amount will vary with the particular disorder being treated, the condition of the patient, the route of administration, the dosage form, the judgment of the practitioner, and other factors. The amounts are determined by generally best techniques, based on the disclosure, based on other factors known to those skilled in the art.
The compounds of the present invention may be included in therapeutic compositions. Such therapeutic agents are used in combination with a therapeutically acceptable delivery vehicle or carrier.
Pharmaceutically acceptable delivery vehicles include solvents, dispersion media, coatings, antibacterial agents, antifungal agents, osmotic agents, and absorption delaying agents suitable for administering the agent. The vehicle may also comprise another active or inert ingredient.
The efficacy of the compounds of the invention, for example, when ED50 (a therapeutically effective dose in 50% of the population) is to be determined, can be determined by in vitro assays such as cell culture, or by standard therapeutic methods in laboratory animals, in accordance with the disclosure.
The data obtained from the in vitro assays and animal studies can be used to adjust the dosage range for use in humans. The dosage will vary depending upon the dosage form and route of administration. For compounds used in the methods of the invention, a therapeutically effective dose can be calculated early in vitro assays. The dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC as determined by in vitro testing50. Using such information, effective doses in humans can be more accurately determined. The level in plasma can be measured by, for example, high performance liquid chromatography and mass spectrometry.
Specific factors, including, but not limited to, the severity of the disease or disorder, previous treatment history, the general health and/or age of the mammal, and other diseases present, will have an effect on the dosage and time required to effectively treat the mammal, as is well known to those skilled in the art. Also, treatment of a mammal with a therapeutically effective amount of a compound of the present invention includes, but is not limited to, monotherapy, alternate treatment, and series of treatments.
In particular, the precise amount of the compound administered to the patient is at the discretion of the attendant physician. However, the dosage to be used depends on various factors including the age and sex of the patient, the precise condition to be treated and its severity, and the route of administration.
The compounds of the present invention are conveniently administered in the form of pharmaceutical compositions. Such compositions are conveniently presented for use in admixture with one or more physiologically acceptable carriers or excipients by conventional means. Pharmaceutical compositions comprising the compounds of the invention may also be one of the invention.
The compounds of the invention may be administered as raw chemicals, but are preferably administered in pharmaceutical dosage forms. The dosage form comprises the compound and one or more acceptable carriers and any other therapeutic ingredients. The carrier must be tolerated in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The therapeutic composition is adjusted to meet the target route of administration. Non-limiting examples of routes of administration are non-oral (e.g., intravenous, intradermal, subcutaneous), oral (e.g., ingestion or inhalation), transdermal (topical), mucosal and rectal administration. The liquid or suspension can be prepared by the methods described in the following documents: remington's Pharmaceutical Sciences (18 th edition, Gennaro, ed., Mack Publishing co., Easton, PA, (1990)).
The optimal route depends, for example, on the condition and disease of the recipient. The dosage form may conveniently be presented as a single dosage form and may be prepared by methods well known in the art of pharmacy. All methods include the step of bringing into association the compound ("active ingredient") with the carrier which is comprised of one or more accessory ingredients. In general, dosage forms are prepared by combining the active ingredient either with a liquid carrier or a finely divided solid carrier, or both, homogeneously and finely, and then shaping the product, as desired, into the desired dosage form.
Dosage forms suitable for oral administration may be provided as: individual units such as capsules, cachets, or tablets (e.g., chewable tablets for pediatric administration, among others) each containing a specified amount of the active ingredient; a powder or granules; a liquid formulation or suspension in an aqueous liquid or a non-aqueous liquid; or liquid concentrate of oil in water or liquid concentrate of water in oil. The active ingredient may also be provided as a bolus, electuary or paste.
Tablets may be prepared by compression or molding with any one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing state, for example, as a powder or granules, in admixture with any binders, lubricants, inert diluents, lubricating surfactants or dispersing agents. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or modified release of the active ingredient therein.
The non-oral administration preparation comprises: aqueous and non-aqueous sterile injection solutions (which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the recipient); and aqueous and non-aqueous sterile suspensions which may contain thickening agents for the suspension. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition ready for addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind described.
Formulations for rectal administration may be presented as suppositories using conventional carriers such as cocoa butter, hard fat or polyethylene glycol.
Formulations for topical administration to the mouth (e.g. buccal or sublingual) include tablets (lozenes) comprising the active ingredient in a base material (e.g. sucrose and acacia gum or xanthan gum) with a fragrance added, and pastilles (pastilles) comprising the active ingredient in a base material (e.g. gelatin and glycerol or sucrose and acacia gum).
The compounds of the present invention or pharmaceutically acceptable salts thereof may also be formulated as implants. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g., acceptable emulsions in oils) or ion exchange resins or may be formulated as sparingly soluble derivatives such as a sparingly soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may contain other agents conventional in the art, for example flavouring agents, suitable for oral administration, depending on the type of formulation concerned.
The present invention relates to combining individual pharmaceutical compositions in a kit format. The kit comprises 2 individual pharmaceutical compositions; a compound of the invention, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and 2 therapeutic agents described in the present application. The kit includes containers such as vials or foil packets containing each composition, but the compositions may be contained in a single, undivided container. The kit format is particularly advantageous when the components are preferably administered in different modes of administration (e.g., oral and non-oral), at different dosing intervals, or when the prescribing physician titrates the components of the composition.
An example of such a reagent kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs are generally constructed from a sheet of relatively rigid material wrapped in a foil of transparent plastic material. In the packaging process, a concave part is formed on the plastic foil. The recess has the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in the recess, and the plastic foil is sealed with respect to the rigid sheet on the foil surface on the opposite side of the direction in which the recess is formed. As a result, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the sheet can be removed from the blister pack by applying pressure to the recesses by hand to form openings in the sheet at the positions of the recesses. Subsequently, the tablet or capsule can be taken out through the upper opening.
Exemplary methods of combination therapy
In certain embodiments, the methods for the present application comprise administering a compound of the invention in combination with one or more 2 nd active agents, or/and in combination with radiation therapy or surgery. Administration of the compound of the invention and the 2 nd active agent to a patient may occur simultaneously or sequentially by the same or different routes of administration. The appropriateness of a particular route of administration for a particular active agent depends on the active agent itself (e.g., whether it can be administered orally without decomposition prior to entering the bloodstream) and the disease to be treated. The recommended route of administration for the 2 nd active agent is well known to those skilled in the art. For example, the references: physicians' Desk Reference.
In one embodiment, the compound of the invention or the 2 nd active agent is injected 1 or 2 times intravenously or subcutaneously in an amount of about 0.1 to about 3,000mg, preferably about 1 to about 1,000mg, more preferably about 5 to about 500mg, even more preferably about 10 to about 375mg, and most preferably about 50 to about 200mg for 1 day.
In another embodiment, the present application provides a method of treating, preventing and/or managing a plurality of diseases resulting from abnormal gastrointestinal motility, the method comprising combining a compound of the invention with conventional therapy (e.g., before, during or after), including but not limited to other non-pharmacogenomic therapies currently used to treat, prevent or manage a plurality of diseases resulting from abnormal gastrointestinal motility. Without being bound by theory, it is believed that the compounds of the present invention provide additive or synergistic effects when given concurrently with such conventional therapies.
In certain embodiments, the 2 nd active agent is administered with a compound of the invention or delayed for 1-50 hours. In certain embodiments, the 2 nd active agent is administered 1-50 hours later after the initial administration of the compound of the invention. In another embodiment, the compound of the invention is administered 1-50 hours later after the first 2 active agent. In some embodiments, the delay time is 24 hours.
In one embodiment, the compounds of the present invention may be administered alone or in combination with the 2 nd active agent disclosed herein in an amount of about 0.1 to about 3,000 mg/day before, during or after conventional therapy.
In another embodiment, a method for the present application comprises: a) administering to a patient in need thereof a dose of about 0.1 to about 3,000 mg/day; and b) administering a therapeutically effective amount of a 2 nd active agent, such as an adjuvant.
The administration mode of the compound of the present invention and the concomitant drug is not particularly limited, and it is sufficient to combine the compound of the present invention and the concomitant drug at the time of administration. Examples of such administration are the following:
(1) administration of a single formulation resulting from simultaneous processing of the compound of the invention and concomitant drug; (2) 2 formulations, prepared separately from the compound of the invention and the concomitant drug, are administered simultaneously by the same route of administration; (3) 2 formulations obtained by separately formulating the compound of the present invention and the concomitant drug are administered with delay by the same route of administration; (4) 2 preparations obtained by separately formulating the compound of the present invention and the concomitant drug are administered simultaneously by different administration routes; (5) 2 preparations prepared from the compound of the present invention and the concomitant drug separately are administered with delay by different administration routes (for example, administration of the compound of the present invention followed by administration of the concomitant drug, or vice versa), and the like. In the following description, these administration modes are collectively referred to as concomitant drugs of the present invention.
When the compounds of the invention are used in combination with one or more other therapeutic agents (2 nd active agents), the compounds of the invention may be administered sequentially or simultaneously by a convenient route.
The above-mentioned compositions may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a pharmaceutically acceptable carrier or excipient as defined above in combination with the composition are additional embodiments of the present invention. The components of the composition may be administered in a single or combined pharmaceutical formulation at one time or simultaneously.
When a compound of the invention is used in combination with a 2 nd therapeutic agent for the same disease, the dose of each compound may be different from the dose when the compound is used alone. Suitable dosages will be readily appreciated by those skilled in the art.
Preferred unit dosage forms are those containing the active ingredient in a 1 day effective dose as described herein, or appropriate parts thereof. For example, the recommended 1-day dose of the compounds of the present invention is preferably from about 0.1mg to about 3,000mg per day, more preferably from about 1mg to about 1,000mg per day. As described above, the dose varies depending on the condition of each patient, but is not limited thereto.
Suitable subjects to be administered the compounds of the present invention or pharmaceutical compositions containing the compounds are mammals including humans. Among them, mammals suffering from various diseases induced by gastric acid abnormality are preferable. Mammals with higher gastric acid pH due to inhibited gastric acid secretion are even more so.
{ example }
The compounds described in the present invention are generally known, and can be synthesized by known methods. The following patent applications are mentioned, for example, in WO97/24369, WO1998/008492, WO1999/058501, WO2000/01726, WO2000/74702 and WO 2008/100448.
A compound A: 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide.
Compound B: 2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide.
Compound C: anarelin, 2-amino-N- [ (1R) -2- [ (3R) -3-benzyl-3- (N, N' -trimethylhydrazinocarbonyl) piperidin-1-yl ] -1- (1H-indol-3-ylmethyl) -2-oxoethyl ] -2-methylpropanamide.
Compound D: ST-1141, also known as RC-1141, (E) -N- ((R) -3- ([1,1' -biphenyl ] -4-yl) -1- (((R) -1- (4-hydroxypiperidin-1-yl) -1-oxo-3-phenylpropan-2-yl) (methyl) amino) -1-oxopropan-2-yl) -4- (1-aminocyclobutyl) -N-methylbut-2-enamide.
Compound E: ulimorelin, (2R,5S,8R,11R) -5-cyclopropyl-11- (4-fluorobenzyl) -2,7, 8-trimethyl-4, 5,7,8,10,11,13,14,15, 16-decahydro-2H-benzo [ q ] [1,4,7,10,13] oxazol tetraazacyclooctadiene-6, 9,12(3H) -trione.
Compound F: ipamorelin, (S) -6-amino-2- ((R) -2- ((S) -2- (2-amino-2-methylpropanamido) -3- (1H-imidazol-5-yl) propanamido) -3- (naphthalen-2-yl) propanamido) -3-phenylpropanamide.
Example 1
Determination of pH in dog stomach
Utilization of male beagle dogs. A metal cannula is surgically inserted into the left side of the abdomen at the very bottom of the stomach tissue region near the distal greater curvature. The intragastric pH is continuously measured with a flexible pH electrode inserted through the stomach . The vehicle or drug is administered orally to the dog. The results are shown in FIG. 1.
Example 2
Compound a at 3mg/kg was orally administered to dogs by a method similar to that described in example 1. The results are shown in FIG. 2. The gastric pH was between 2 and 7 in vehicle-treated conscious dogs. In both dogs administered compound a, the intragastric pH of dogs rapidly decreased after administration, with the lower pH being maintained below about 2.5 for more than 3 hours.
Example 3
Compound B was orally administered to dogs by a method similar to that described in example 1. The intragastric pH of the dogs decreased immediately after dosing, maintaining a lower pH for more than 3 hours.
Example 4
Compound C was orally administered to dogs by a method similar to that described in example 1. The intragastric pH of the dogs decreased immediately after dosing, maintaining a lower pH for more than 3 hours.
Example 5
Compound D was orally administered to dogs by a method similar to that described in example 1. The intragastric pH of the dogs decreased immediately after dosing, maintaining a lower pH for more than 3 hours.
Example 6
Compound E was orally administered to dogs by a method similar to that described in example 1. The intragastric pH of the dogs decreased immediately after dosing, maintaining a lower pH for more than 3 hours.
Example 7
Compound F was orally administered to dogs by a method similar to that described in example 1. The intragastric pH of the dogs decreased immediately after dosing, maintaining a lower pH for more than 3 hours.
Claims (23)
1. Use of one or more substances selected from the group consisting of a compound of formula (I), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 1}
In the above formula:
e is 0 or 1;
n and w are each independently 0,1 or 2, provided that w and n cannot both be 0;
y is oxygen or sulfur;
R1is hydrogen, -CN, - (CH)2)qN(X6)C(O)X6、-(CH2)qN(X6)C(O)(CH2)t-A1、-(CH2)qN(X6)SO2(CH2)t-A1、-(CH2)qN(X6)SO2X6、-(CH2)qN(X6)C(O)N(X6)(CH2)t-A1、-(CH2)qN(X6)C(O)N(X6)(X6)、-(CH2)qC(O)N(X6)(X6)、-(CH2)qC(O)N(X6)(CH2)t-A1、-(CH2)qC(O)OX6、-(CH2)qC(O)O(CH2)t-A1、-(CH2)qOX6、-(CH2)qOC(O)X6、-(CH2)qOC(O)(CH2)t-A1、-(CH2)qOC(O)N(X6)(CH2)t-A1、-(CH2)qOC(O)N(X6)(X6)、-(CH2)qC(O)X6、-(CH2)qC(O)(CH2)t-A1、-(CH2)qN(X6)C(O)OX6、-(CH2)qN(X6)SO2N(X6)(X6)、-(CH2)qS(O)mX6、-(CH2)qS(O)m(CH2)t-A1、-(C1-C10) Alkyl, - (CH)2)t-A1、-(CH2)q-(C3-C7) Cycloalkyl, - (CH)2)q-Y1-(C1-C6) Alkyl, - (CH)2)q-Y1-(CH2)t-A1Or- (CH)2)q-Y1-(CH2)t-(C3-C7) A cycloalkyl group;
wherein, in R1In the definition of (A), the alkyl and cycloalkyl groups are optionally substituted by (C)1-C4) Alkyl, hydroxy, (C)1-C4) Alkoxy, carboxy, -CONH2、-S(O)m(C1-C6) Alkyl, -CO2(C1-C4) Alkyl esters, 1H-tetrazol-5-yl or 1,2 or 3 fluoro substitutions; y is1Is O, S (O)m、-C(O)NX6-、-CH＝CH-、-C≡C-、-N(X6)C(O)-、-C(O)NX6-、-C(O)O-、-OC(O)N(X6) -or-oc (o) -;
q is 0,1, 2,3 or 4;
t is 0,1, 2 or 3;
m is 0,1 or 2;
said (CH)2)qGroup and (CH)2)tThe radicals may be optionally substituted by hydroxy or (C)1-C4) Alkoxy, carboxy, -CONH2、-S(O)m-(C1-C6) Alkyl, -CO2(C1-C4) Alkyl esters, 1H-tetrazol-5-yl, 1,2 or 3 fluoro, or 1 or 2 (C)1-C4) Alkyl substitution;
R2is hydrogen, (C)1-C8) Alkyl, - (C)0-C3) Alkyl radical- (C)3-C8) Cycloalkyl, - (C)1-C4) alkyl-A1Or A1；
Wherein, in R2In the definition of (1), the alkyl and the cycloalkyl are optionally substituted by hydroxy, -C (O) OX6、-C(O)N(X6)(X6)、-N(X6)(X6)、-S(O)m(C1-C6) Alkyl, -C (O) A1、-C(O)(X6)、CF3CN or 1,2 or 3 halogen substitutions;
R3is A1、(C1-C10) Alkyl, - (C)1-C6) alkyl-A1、-(C1-C6) Alkyl radical- (C)3-C7) Cycloalkyl, - (C)1-C5) alkyl-X1-(C1-C5) Alkyl, - (C)1-C5) alkyl-X1-(C0-C5) alkyl-A1Or- (C)1-C5) alkyl-X1-(C1-C5) Alkyl radical- (C)3-C7) A cycloalkyl group;
wherein, in R3In the definition of (1), the alkyl group is optionally substituted by-S (O)m(C1-C6) Alkyl, -C (O) OX31,2,3,4 or 5 halogens, or 1,2 or 3 OX3Substitution;
X1is O, S (O)m、-N(X2)C(O)-、-C(O)N(X2)-、-OC(O)-、-C(O)O-、-CX2＝CX2-、-N(X2)C(O)O-、-OC(O)N(X2) -or-C ≡ C-;
R4is hydrogen, (C)1-C6) Alkyl or (C)3-C7) Cycloalkyl, or, R4And R3And the carbon atoms to which they are bonded form (C)5-C7) Cycloalkyl group, (C)5-C7) Cycloalkenyl, partially or fully saturated 4-to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or R4Is a bicyclic ring system consisting of a partially saturated or fully saturated 5-or 6-membered ring fused to a partially saturated, fully unsaturated or fully saturated 5-or 6-membered ring and optionally having 1-4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X4is hydrogen or (C)1-C6) Alkyl, or, X4And R4And with X4A nitrogen atom bound to and R4The bonded carbon atoms together form a 5-7 membered ring;
R6is a key or
{ chemical formula 2}
Wherein a and b are independently 0,1, 2 or 3;
X5and X5aEach independently selected from hydrogen, trifluoromethyl, A1And optionally substituted (C)1-C6) Alkyl groups;
at X5And X5aIn the definition of (1), the optionally substituted (C)1-C6) Alkyl is optionally selected from A1、OX2、-S(O)m(C1-C6) Alkyl, -C (O) OX2、(C3-C7) Cycloalkyl, -N (X)2)(X2) and-C (O) N (X)2)(X2) Substituted with a substituent in the group formed;
wherein, the compound contains X5Or X5aWith carbon containing R7And R8Together form 1 or 2 alkylene bridges, wherein each alkylene bridge contains 1 to 5 carbon atoms, with the proviso that when 1 alkylene bridge is formed, X5Or X5aMay be on the carbon atom but not both, and R7Or R8May be on the nitrogen atom but not both, further provided that, when 2 alkylene bridges are formed, X5And X5aCannot be on the carbon atom, and R7And R8Cannot be located on the nitrogen atom; or
X5And X5aAnd together with the carbon atom to which they are bonded form a partially or fully saturated 3-to 7-membered ring, or a partially or fully saturated 4-to 8-membered ring having 1-4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or
X5And X5aTogether with the carbon atoms to which they are bonded, form a bicyclic ring system consisting of a partially or fully saturated 5-or 6-membered ring optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, and fused to an optionally having 1 to 4 heteroatoms independentlyA partially saturated, fully saturated or fully unsaturated 5-or 6-membered ring of heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen;
Z1is a bond, O or N-X2Provided that when a and b are both 0, Z1Is not N-X2Or O;
R7and R8Independently hydrogen or optionally substituted (C)1-C6) An alkyl group;
wherein, in R7And R8In the definition of (1), the optionally substituted (C)1-C6) Alkyl is independently optionally substituted by A1、-C(O)O-(C1-C6) Alkyl, -S (O)m(C1-C6) Alkyl, 1-5 halogens, 1-3 hydroxyls, 1-3-O-C (O) (C)1-C10) Alkyl or 1-3 (C)1-C6) Alkoxy substitution; or
R7And R8May be taken together to form- (CH)2)r-L-(CH2)r-; wherein L is C (X)2)(X2)、S(O)mOr N (X)2)；
In each case, A1Independently is (C)5-C7) Cycloalkenyl, phenyl or a substituent formed by eliminating hydrogen from a partially saturated, fully saturated or fully unsaturated 4-to 8-membered ring, a bicyclic system consisting of a partially saturated, fully unsaturated or fully saturated 5-or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5-or 6-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
in each case, when A1When they are bicyclic, A1Optionally substituted on 1 or any 2 rings with up to 3 substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3、OCF2H、CF3、CH3、OCH3、-OX6、-C(O)N(X6)(X6)、-C(O)OX6Oxo, and (C)1-C6) Alkyl, nitro, cyano, benzyl, -S (O)m(C1-C6) Alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkoxy, halophenyl, methylenedioxy, -N (X)6)(X6)、-N(X6)C(O)(X6)、-SO2N(X6)(X6)、-N(X6)SO2-phenyl, -N (X)6)SO2X6、-CONX11X12、-SO2NX11X12、-NX6SO2X12、-NX6CONX11X12、-NX6SO2NX11X12、-NX6C(O)X12Imidazolyl, thiazolyl or tetrazolyl, with the proviso that when A1Optionally substituted with methylenedioxy, it may be substituted with only 1 methylenedioxy;
wherein, X11Is hydrogen or optionally substituted (C)1-C6) An alkyl group;
at X11In the definition of (1), the optionally substituted (C)1-C6) Alkyl is independently optionally substituted by phenyl, phenoxy, (C)1-C6) Alkoxycarbonyl, -S (O)m(C1-C6) Alkyl, 1-5 halogens, 1-3 hydroxyls, 1-3 (C)1-C10) Alkanoyloxy or 1-3 (C)1-C6) Alkoxy substitution;
X12is hydrogen, (C)1-C6) Alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, with the proviso that when X12When not hydrogen, X12Optionally 1-3 independently selected from Cl, F, CH3、OCH3、OCF3And CF3Substituted with a substituent in the group formed; or
X11And X12Together form- (CH)2)r-L1-(CH2)r-; wherein L is1Is C (X)2)(X2)、O、S(O)mOr N (X)2)；
In each case, r is independently 1,2, or 3;
in each case, X2Independently hydrogen, optionally substituted (C)1-C6) Alkyl or optionally substituted (C)3-C7) Cycloalkyl, wherein at X2In the definition of (1), the optionally substituted (C)1-C6) Alkyl and optionally substituted (C)3-C7) Cycloalkyl is independently optionally substituted by-S (O)m(C1-C6) Alkyl, -C (O) OX31-5 halogens or 1-3 OX3Substitution;
in each case, X3Independently is halogen or (C)1-C6) An alkyl group;
X6independently hydrogen, optionally substituted (C)1-C6) Alkyl, (C)2-C6) Halogenated alkyl, optionally substituted (C)3-C7) Cycloalkyl group, (C)3-C7) -halogenated cycloalkyl, wherein in X6In the definition of (1), (C) optionally substituted1-C6) Alkyl and optionally substituted (C)3-C7) Cycloalkyl is independently optionally substituted by 1 or 2 (C)1-C4) Alkyl, hydroxy, (C)1-C4) Alkoxy, carboxyl, CONH2、-S(O)m(C1-C6) Alkyl, carboxylic ester group, (C)1-C4) Alkylcarboxy ester or 1H-tetrazol-5-yl substitution; or, when there are 2X's on 1 atom6Group and 2X6Independently is (C)1-C6) When alkyl, the 2 is (C)1-C6) Alkyl optionally bonded to said 2X6The bonded atoms together forming any of oxygen, sulfur, or NX74-to 9-membered ring of (a);
X7is hydrogen or optionally substituted by hydroxy (C)1-C6) An alkyl group; in each case, m is independently 0,1 or 2;
with the following conditions:
X6and X12When using C (O) X6、C(O)X12、SO2X6Or SO2X12Formally linked to C (O) or SO2When it is not hydrogen;
when R is6When it is a bond, L is N (X)2) In- (CH)2)r-L-(CH2)r-each r is independently 2 or 3; and is
C*Representing an asymmetric carbon atom.
2. Use of one or more substances selected from the group consisting of a compound of formula (II), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 3}
In the above formula:
R1is- (C)1-C3) Alkyl-phenyl, - (C)1-C3) Alkyl-pyridyl, - (C)1-C3) Alkyl-quinolyl or- (C)1-C3) Alkyl-thiazolyl, wherein, R1Wherein the phenyl group is optionally substituted by 1 or 2 groups selected from the group consisting of halo, CF3、CH3And phenyl is substituted with a substituent in the group consisting of;
R2is- (C)1-C4) Alkyl or- (C)1-C4) alkyl-CF3；
R3Is- (C)1-C4) Alkyl indolyl, - (C)1-C4) Alkyl phenyl, - (C)1-C4) alkyl-O- (C)1-C4) alkyl-Ar, - (C)1-C4) alkyl-S- (C)1-C4) alkyl-Ar, wherein Ar is phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl or benzisoxazolyl, and the Ar is optionally substituted by 1 or 2 groups selected from halogen and OCF3、CF3And CH3Substituted with a substituent in the group formed; and is
R6is-C (X)5)(X5) Wherein X is5Is- (C)1-C6) An alkyl group.
3. Use according to claim 1 or 2, wherein the compound is selected from the group consisting of:
2-amino-N- [1- (3a- (R, S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridine-5-carbonyl) -4-phenyl (R) -butyl ] isobutyramide;
2-amino-N- [1- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridine-5-carbonyl) -4-phenyl (R) -butyl ] isobutyramide;
2-amino-N- [1- (3a- (S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridine-5-carbonyl) -4-phenyl (R) -butyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-ethyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-3-oxo-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-3-oxo-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydro-pyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-3-oxo-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (3a- (R, S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (3a- (R) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (3a- (S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-tert-butyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-2-tert-butyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-2-tert-butyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R, S) -benzyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (R) -benzyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [2- (3a- (S) -benzyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3 a- (R) -pyridin-2-ylmethyl-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3 a- (S) -pyridin-2-ylmethyl-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -2-oxo-ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (3-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (3-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (3-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-dichloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-dichloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-dichloro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-thiophen-2-ylmethoxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,5, 7-hexahydropyrazolo [3,4-c ] pyridin-6-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-thiophen-2-ylmethoxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,5, 7-hexahydropyrazolo [3,4-c ] pyridin-6-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (4-chloro-thiophen-2-ylmethoxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,5, 7-hexahydropyrazolo [3,4-c ] pyridin-6-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R, S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (S) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide;
2-amino-N- [2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (3, 4-difluoro-benzyloxymethyl) -2-oxo-ethyl ] -2-methyl-propionamide;
2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (3, 4-difluoro-benzyloxymethyl) -2-oxo-ethyl ] -2-methyl-propionamide; and
2-amino-N- [2- (3a- (S) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) - (3, 4-difluoro-benzyloxymethyl) -2-oxo-ethyl ] -2-methyl-propionamide; or
A pharmaceutically acceptable salt thereof.
4. Use according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of:
2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, 3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl ] isobutyramide;
2-amino-N- [1- (R) - (2, 4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3 a- (R) -pyridin-2-ylmethyl-2- (2,2, 2-trifluoro-ethyl) -2,3,3a,4,6, 7-hexahydropyrazolo [4,3-c ] pyridin-5-yl) -ethyl ] -2-methyl-propionamide; and
a pharmaceutically acceptable salt thereof.
5. Use of one or more substances selected from the group consisting of a compound of formula (III), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 4}
In the above formula:
R1is hydrogen or C optionally substituted by more than 1 aryl or heteroaryl1-6-an alkyl group;
a and d are each independently 0,1, 2 or 3;
b and c are each independently 0,1, 2,3,4 or 5, provided that b + c is 3,4 or 5;
d is R2-NH-(CR3R4)e-(CH2)f-M-(CHR5)g-(CH2)h-，
Wherein R is2、R3、R4And R5Independently hydrogen, or C optionally substituted with 1 or more halogen, amino, hydroxy, aryl or heteroaryl1-6-an alkyl group; or
R2And R3Or R2And R4Or R3And R4Can form- (CH) at will2)i-U-(CH2)j-, wherein i and j are independently 1 or 2, U is-O-, -S-, or a bond;
h and f are independently 0,1, 2 or 3;
g and e are independently 0 or 1;
m is a bond, -CR6＝CR7-, arylene, heteroarylene, -O-or-S-;
R6and R7Independently hydrogen, or C optionally substituted by 1 or more aryl or heteroaryl groups1-6-an alkyl group;
g is-O- (CH)2)k-R8、
{ chemical formula 5}
J is-O- (CH)2)lR13、
{ chemical formula 6}
Wherein R is8、R9、R10、R11、R12、R13、R14、R15、R16And R17Each independently is hydrogen, halogen, aryl, heteroaryl, C1-6-alkyl or C1-6-an alkoxy group;
k and l are independently 0,1 or 2;
e is-CONR18R19、-COOR19、-(CH2)m-NR18SO2R20、-(CH2)m-NR18COR20、-(CH2)m-OR19、-(CH2)m-OCOR20、-CH(R18)R19、-(CH2)m-NR18-CS-NR19R21Or- (CH)2)m-NR18-CO-NR19R21(ii) a Or
E is-CONR22NR23R24，
Wherein R is22Is hydrogen, C optionally substituted by more than 1 aryl or heteroaryl1-6-alkyl, or optionally 1 or more C1-6-alkyl-substituted aryl or heteroaryl; r23Is C optionally substituted by 1 or more aryl or heteroaryl groups1-6-alkyl, or C1-7-an acyl group; and, R24Is hydrogen, C optionally substituted by more than 1 aryl or heteroaryl1-6-an alkyl group; or optionally 1 or more C1-6-alkyl-substituted aryl or heteroaryl; or
R22And R23May form, together with the nitrogen atom to which they are bonded, optionally more than 1C1-6-alkyl-, halogen-, amino-, hydroxy-, aryl-or heteroaryl-substituted heterocyclic ring systems; or
R22And R24May form, together with the nitrogen atom to which they are bonded, optionally more than 1C1-6-alkyl-, halogen-, amino-, hydroxy-, aryl-or heteroaryl-substituted heterocyclic ring systems; or
R23And R24May form, together with the nitrogen atom to which they are bonded, optionally more than 1C1-6-alkyl-, halogen-, amino-, hydroxy-, aryl-or heteroaryl-substituted heterocyclic ring systems;
wherein m is 0,1, 2 or 3,
R18、R19and R21Independently hydrogen or optionally halogen, -N (R)25)R26Substituted C1-6-alkyl, wherein R25And R26Independently is hydrogen or C1-6-an alkyl group; hydroxy, C1-6-alkoxy, C1-6Alkoxycarbonyl, C1-6-an alkylcarbonyloxy group or an aryl group; or
R19Is composed of
{ chemical formula 7}
Wherein the content of the first and second substances,
q is-CH < or-N <,
k and L are independently-CH2-、-CO-、-O-、-S-、-NR27-or a bond(s),
wherein R is27Is hydrogen or C1-6-an alkyl group;
n and o are independently 0,1, 2,3 or 4;
R20is C1-6-alkyl, aryl or heteroaryl;
provided that, if M is a bond, E is-CONR22NR23R24。
6. The use according to claim 5, wherein the compound is of the following formula (IV).
{ chemical formula 8}
7. Use of one or more substances selected from the group consisting of a compound of formula (V), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 9}
In the above formula:
R1is hydrogen or C1-6-an alkyl group;
R2is hydrogen or C1-6-an alkyl group;
l is
{ chemical formula 10}
Wherein R is4Is hydrogen or C1-6-an alkyl group;
p is 0 or 1;
q, s, t, u are each independently 0,1, 2,3 or 4;
r is 0 or 1;
q + r + s + t + u is 0,1, 2,3 or 4;
R9、R10、R11and R12Are each independently hydrogen or C1-6-an alkyl group;
q is > N-R13Or is
{ chemical formula 11}
Wherein o is 0,1 or 2;
t is-N (R)15)(R16) Or a hydroxyl group;
R13、R15and R16Are each independently hydrogen or C1-6-an alkyl group;
R14is hydrogen, aryl or heteroaryl;
g is-O- (CH)2)k-R17、
{ chemical formula 12}
Wherein R is17、R18、R19、R20And R21Each independently is hydrogen, halogen, aryl, heteroaryl, C1-6-alkyl or C1-6-an alkoxy group;
k is 0,1 or 2;
j is-O- (CH)2)lR22、
{ chemical formula 13}
Wherein R is22、R23、R24、R25And R26Each independently is hydrogen, halogen, aryl, heteroaryl, C1-6-alkyl or C1-6-An alkoxy group;
l is 0,1 or 2;
a is 0,1 or 2;
b is 0,1 or 2;
c is 0,1 or 2;
d is 0 or 1;
e is 0,1, 2 or 3;
f is 0 or 1;
R5is hydrogen, or C optionally substituted by 1 or more hydroxy, aryl or heteroaryl groups1-6-an alkyl group;
R6and R7Each independently is hydrogen, or C optionally substituted with 1 or more halogen, amino, hydroxy, aryl or heteroaryl1-6-an alkyl group;
R8is hydrogen, or C optionally substituted by 1 or more halogen, amino, hydroxy, aryl or heteroaryl1-6-an alkyl group;
R8and R7Or R6And R8Or R7And R8Can form- (CH) at will2)i-U-(CH2)j-, wherein i and j are each independently 1,2 or 3, and U is-O-, -S-, or a bond;
m is arylene, heteroarylene, -O-, -S-or-CR27＝CR28-；
R27And R28Each independently is hydrogen or optionally substituted by 1 or more aryl or heteroaryl groupsSubstituted C1-6-an alkyl group.
8. The use according to claim 7, wherein the compound is of the following formula (VI).
{ chemical formula 14}
9. Use of one or more substances selected from the group consisting of a compound of formula (VII), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 15}
In the above formula:
*represents a carbon atom having R or S configuration when the carbon atom is a chiral carbon atom, R being1And R3One of which is a hydrogen atom and the other is a group of formula (A);
{ chemical formula 16}
R2Is a hydrogen atom, a straight chain or a branched chain C1-C6Alkyl, aryl, heterocyclyl, cycloalkyl, (CH)2)nAryl radicals, (CH)2)n-heterocyclyl (CH)2)nCycloalkyl, methanesulfonyl, benzenesulfonyl, C (O) R8A group or a group of one of formulae (B) to (G);
{ chemical formula 17}
R4Is a hydrogen atom or a straight or branched chain C1-C4-an alkyl group,
R5is a hydrogen atom, a straight chain or a branched chain C1-C4Alkyl, (CH)2)nAryl radicals, (CH)2)n-heterocyclyl (CH)2)n-a cycloalkyl group or an amino group,
R6and R7Each independently being a hydrogen atom or a linear or branched C1-C4-an alkyl group,
R8is straight chain or branched C1-C6-an alkyl group,
R9、R10、R11、R12、R13、R14、R15and R16Each independently being a hydrogen atom or a linear or branched C1-C4-an alkyl group,
m is 0,1 or 2, and n is 1 or 2.
10. The use according to claim 9, wherein the compound is of formula (VIII) below.
{ chemical formula 18}
11. Use of one or more substances selected from the group consisting of a compound of formula (IX), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
{ chemical formula 19}
In the above formula:
R1is hydrogen or the side chain of an amino acid, or, R1And R2Together form a 4-, 5-, 6-, 7-or 8-membered ring optionally containing O, S or N atoms in the ring, wherein the ring is optionally defined as R8Substituted, or, R1And R9Together form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined as R8Substitution;
R2is hydrogen or the side chain of an amino acid, or, R1And R2Together form a 4-, 5-, 6-, 7-or 8-membered ring optionally containing O, S or N atoms in the ring, wherein the ring is optionally defined as R8Substituted, or, R2And R9Together form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined as R8Substitution;
R3is hydrogen or the side chain of an amino acid, or, R3And R4Together form a 3-, 4-, 5-, 6-or 7-membered ring optionally containing an O or S atom in the ring, wherein the ring is optionally defined by R as defined below8Substituted, or, R3And R7Or R3And R11Together form a 4-, 5-, 6-, 7-or-8-membered heterocyclic ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined by R as defined below8Substitution;
R4is hydrogen or the side chain of an amino acid, or, R3And R4Together form a 3-, 4-, 5-, 6-or 7-membered ring optionally containing an O or S atom in the ring, wherein the ring is optionally defined by R as defined below8Substituted, or, R4And R7Or R4And R11Together form a 4-, 5-, 6-, 7-or 8-membered heterocyclic ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined by R as defined below8Substitution；
R5And R6Each independently hydrogen or the side chain of an amino acid, or, R5And R6Together form a 3-, 4-, 5-, 6-, or 7-membered ring optionally containing O, S or N atoms in the ring, wherein the ring is optionally defined as R8Substitution;
R7is hydrogen, C1-C10Alkyl, substituted C1-C10-alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, or, R3And R7Or R4And R7Together form a 4-, 5-, 6-, 7-or 8-membered heterocyclic ring optionally containing O, S or further containing a N atom in the ring, wherein the ring is optionally substituted with R8Substitution;
R8substituted with 1 or more hydrogen atoms in the 3-, 4-, 5-, 6-, 7-or 8-membered ring structure, and independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, mercapto, sulfinyl, sulfonyl and sulfonamido, or, R is a group8Is a fused cycloalkyl, substituted fused cycloalkyl, fused heterocyclyl, substituted fused heterocyclyl, fused aryl, substituted fused aryl, fused heteroaryl, or substituted fused heteroaryl group;
x is O, NR9Or N (R)10)2 +；
Wherein R is9Is hydrogen, C1-C10Alkyl, substituted C1-C10-alkyl, sulfonyl, sulfonamide or amidino, R10Is hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, or, R9And R10Together form a 3-, 4-, 5-, 6-or 7-membered ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined by the definition of R8Substitution;
Z1is O or NR11；
Wherein R is11Is hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, or, R3And R11Or R4And R11Together form a 4-, 5-, 6-, 7-or 8-membered heterocyclic ring optionally containing O, S or further containing the N atom in the ring, wherein the ring is optionally defined by R8Substitution;
Z2is O or NR12,
Wherein R is12Is hydrogen, C1-C10-alkyl or substituted C1-C10-an alkyl group;
m, n and p are each independently 0,1 or 2;
t is a divalent radical of the formula,
-U-(CH2)d-W-Y-Z-(CH2)e-
wherein d and e are each independently 0,1, 2,3,4 or 5; y and Z are each optionally present; u is-CR21R22-or-C (═ O) -, and is bonded to X of formula (IX); w, Y and Z are each independently selected from the group consisting of-O-, -NR-23-、-S-、-SO-、-SO2-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NH-、-NH-C(＝O)-、-SO2-NH-、-NH-SO2-、-CR24R25-, CH ═ CH-, -C ≡ C-having Z or E configuration, and the group consisting of the following cyclic structural formulae:
{ chemical formula 20}
Wherein G is1And G2Each independently is a bond, or is selected from the group consisting of-O-, -NR39-、-S-、-SO-、-SO2-、-C(＝O)-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)NH-、-NH-C(＝O)-、-SO2-NH-、-NH-SO2-、-CR40R41-, a bivalent radical of the group consisting of-CH ═ CH-and-C ≡ C-having the configuration Z or E; g1The group closest to U is bonded thereto; whereinAny carbon atom on the ring not otherwise defined is optionally substituted with N, provided that: the ring must not contain more than 4N atoms; k1、K2、K3、K4And K5Are each independently O, NR42Or S, wherein R42As defined below;
R21and R22Are each independently hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, or, R21And R22Together form a 3-to 12-membered cyclic ring optionally containing 1 or more heteroatoms selected from the group consisting of O, S or N, wherein the ring is optionally defined by R8Substitution;
R23、R39and R42Each independently is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, amidino, sulfonyl or sulfonamido;
R24and R25Are each independently hydrogen, C1-C10Alkyl, substituted C1-C10-alkyl, RAAWherein R isAAIs the side chain of an amino acid, or, R24And R25Together form a 3-to 12-membered cyclic ring optionally containing 1 or more heteroatoms selected from the group consisting of O, S and N; or, R24And R25One of which is hydroxy, alkoxy, aryloxy, amino, mercapto, carbamoyl, amidino, ureido or guanidine, the other is hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, R24And R25Except where the bonded carbon is also bonded to another heteroatom;
R26、R31、R35and R38Each of which is optionally substituted, when present, by 1 or more hydrogen atoms on the indicated ring, and is independently selected from the group consisting of halogen, trifluoromethyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and mixtures thereof,Substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, cyano, nitro, mercapto, sulfinyl, sulfonyl and sulfonamido;
R27optionally, substituted, when present, with 1 or more hydrogen atoms on the indicated ring, each independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, mercapto, sulfinyl, sulfonyl, and sulfonamido;
R28、R29、R30、R32、R33、R34、R36and R37Optionally present, wherein the carbon atoms bonded to them in the ring do not have a double bond, 2 groups optionally present, wherein if present, each group substitutes 1 hydrogen present in the ring, or wherein the carbon atoms bonded to them in the ring do not have a double bond, 1 or 2 of the 2 hydrogen atoms in the ring are substituted, wherein each group is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, mercapto, sulfinyl, sulfonyl, sulfonamido and halogen (when only a double bond is present), and wherein
R40And R41Are each independently hydrogen, C1-C10Alkyl, substituted C1-C10-alkyl, R as defined aboveAAOr, R40And R41Together form a ring optionally containing 1 or more heteroatoms selected from the group consisting of O, S and NA 3-to 12-membered cyclic ring of (a), wherein the ring is optionally R as defined above8Substituted, or, R40And R41One of which is hydroxy, alkoxy, aryloxy, amino, mercapto, carbamoyl, amidino, ureido or guanidino, and the other is hydrogen, C1-C10-alkyl or substituted C1-C10-alkyl, R40And R41Except where the bonded carbon is also bonded to another heteroatom;
with the proviso that T is not an amino acid residue, a dipeptide fragment, a tripeptide fragment or comprises standard ammonia
Higher order peptide fragments of an amino acid.
12. The use according to claim 11, wherein the compound is selected from the compounds of the following formulae (Xa), (Xb) and (Xc).
{ chemical formula 21}
13. Use of one or more substances selected from the group consisting of a compound of formula (XI), a racemic-diastereomeric mixture, an optical isomer of said compound, a pharmaceutically-acceptable salt thereof, and a prodrug thereof, in the manufacture of a medicament for the treatment of achlorhydria in a human or animal:
A-B-C-D(-E)p (XI)
in the above formula:
p is 0 or 1;
a is hydrogen or R1-(CH2)q-(X)r-(CH2)s-CO-, wherein,
q is 0 or an integer of 1 to 5;
r is 0 or 1;
s is 0 or an integer from 1 to 5;
R1is hydrogen, imidazolyl, guanidino, piperazinyl, morpholinyl, piperidinyl or N (R)2)-R3Wherein R is2And R3Each independently is hydrogen or C optionally substituted with 1 or more hydroxy, pyridyl or furyl groups1-C10-an alkyl group; and is
When r is 1, X is-NH-, -CH2-、-CH＝CH-、
{ chemical formula 22}
Wherein R is16And R17Are each independently hydrogen or C1-C10-an alkyl group;
b is (G)t-(H)uWherein, in the step (A),
t is 0 or 1;
u is 0 or 1;
g and H are amino acid residues selected from the group consisting of natural L-amino acids or their corresponding D-isomers and unnatural amino acids such as 1, 4-diaminobutyric acid, amino-isobutyric acid, 1, 3-diaminopropionic acid, 4-aminophenylalanine, 3-pyridylalanine, 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, 1,2,3, 4-tetrahydronorhalman-3-carboxylic acid, N-methylanthranilic acid, anthranilic acid, N-benzylglycine, 3-amino-3-methylbenzoic acid, 3-amino-3-methylbutyric acid, sarcosine, hexahydronicotinic acid or isohexahydropyronicotinic acid;
when t and u are both 1, the amide bond between G and H is optionally Y-NR18-substituted, wherein Y is-CO-or-CH2-，R18Is hydrogen, C1-C10-alkyl or lower aralkyl;
c is a chemical formula of-NH-CH ((CH)2)w-R4) -a D-amino acid residue of CO-, wherein w is 0,1 or 2; and is
R4Is selected from the group consisting of
{ chemical formula 23}
Optionally halogen, C1-C10Alkyl radical, C1-C10-alkoxy, C1-C10-alkylamino, amino or hydroxy substitution;
when p is 1, D is of the formula-NH-CH ((CH)2)k-R5) A D-amino acid residue of-CO-, or, when p is 0, D is-NH-CH ((CH)2)l-R5)-CH2-R6or-NH-CH ((CH)2)m-R5)-CO-R6Wherein, in the step (A),
k is 0,1 or 2;
l is 0,1 or 2;
m is 0,1 or 2;
R5is selected from the group consisting of
{ chemical formula 24}
Each of which is optionally substituted with halogen, alkyl, alkoxyamino or hydroxy; and is
R6Is piperazinyl, morpholinyl, piperidinyl, -OH or-N (R)7)-R8Wherein R is7And R8Are each independently hydrogen or C1-C10-an alkyl group;
when p is 1, E is-NH-CH (R)10)-(CH2)V-R9Wherein v is 0 or an integer of 1 to 8;
R9is hydrogen, imidazolyl, guanidino, piperazinyl, morpholinyl, piperidinyl,
{ chemical formula 25}
Wherein n is 0,1 or 2, R19Is hydrogen or C1-C10-an alkyl group,
{ chemical formula 26}
Wherein o is an integer of 1 to 3; or
N(R11)-R12Wherein R is11And R12Are each independently hydrogen or C1-C10-alkyl, or
{ chemical formula 27}
Optionally substituted with halogen, alkyl, alkoxy, amino, alkylamino, hydroxy, or a rearrangement product of amino and a residue formed from a pyranohexose or a pyranosyl-pyranohexose with hydrogen eliminated, respectively;
when p is 1, R10Selected from the group consisting of-H, -COOH, -CH2-R13、-CO-R13or-CH2-OH, wherein,
R13is piperazinyl, morpholinyl, piperidinyl, -OH or-N (R)14)-R15Wherein R is14And R15Are each independently hydrogen or C1-C10-an alkyl group;
the amide bond between B and C, or between A and C when t and u are both 0, is optionally substituted by R18Or Y-NR18-substituted, wherein Y is-CO-or-CH2-，R18Is hydrogen, C1-C10-alkyl or lower aralkyl, or, when p is 1, the amide bond between D and E is optionally substituted by Y-NR18-substituted, wherein Y and R18As defined above.
14. The use as in claim 13, wherein the compound is of formula (XII) below.
{ chemical formula 28}
15. Use according to any one of claims 1 to 14, wherein the molecular weight of the compound is less than 800.
16. The use according to any one of claims 1 to 15, wherein the achlorhydria is age-related achlorhydria with an aging process; chronic gastritis-related achlorhydria; anemic achlorhydria with anemia symptoms; gastric segmental resection-associated achlorhydria; calcium absorption-associated achlorhydria; vitamin D absorption-associated achlorhydria; calcitonin synthesis-related achlorhydria; and drug-induced achlorhydria.
17. Use of a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in combination with one or more 2 nd active agents.
18. The use of claim 17, wherein the 2 nd active agent is selected from any one of the following:
(i) histamine H2Receptor antagonists, (ii) proton pump inhibitors, (iii) oral antacid mixtures, (iv) mucosal protectants, (v) anti-gastric ulcers, (vi)5-HT3 antagonists, (vii)5-HT4 agonists, (viii) laxatives, (ix) GABAB agonists, (x) GABAB antagonists, (xi) calcium channel blockers, (xii) dopamine antagonists, (xiii) tachykinin (NK) antagonists, (xiv) helicobacter pylori infectives, (xv) nitric oxide synthase inhibitors, (xvi) capsaicin receptor 1 antagonists, (xvii) muscarinic receptor antagonists, (xviii) calmodulin antagonists, (xviii) potassium channel agonists, (xx) beta-1 agonists, (xxbet) alpha agonists, (xxiii) 2 agonists, (xxiv) endothelin A antagonists, (xxv) opioid mu agonists, (xxvi) Opioid μ antagonists, (xxvii) motilin agonists, (xxviii) ghrelin agonists, (xxix) AchE release agonistsA drug, (xxx) a CCK-B antagonist, (xxxi) a glucagon antagonist, (xxxii) piperacillin, ampicillin hydrochloride, tetracycline, metronidazole, bismuth citrate and bismuth subsalicylate, (xxxiii) a glucagon-like peptide-1 (GLP-1) antagonist, (xxxiv) a small conductance calcium activated potassium channel 3(SK-3) antagonist, (xxxv) an mGluR5 antagonist, (xxxvi) a 5-HT3 agonist, (xxxvii) an mGluR8 agonist, (xxxviii) a chemotherapeutic agent, (xxxix) an immunotherapeutic agent, (xL) a cachexia drug, (xL) a diuretic, and (xLii) an antidepressant.
19. A method of treatment of achlorhydria, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, to a human or animal.
20. A pharmaceutical composition for use in the treatment of achlorhydria, which comprises a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.
21. A kit for the treatment of achlorhydria comprising a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.
22. A kit according to claim 21, comprising a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, at least one 2 nd active agent and a container.
23. A commercial package comprising a pharmaceutical composition comprising a compound as defined in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a written matter associated with said pharmaceutical composition that states that the pharmaceutical composition can or should be used for the treatment of achlorhydria.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261651662P | 2012-05-25 | 2012-05-25 | |
| US61/651,662 | 2012-05-25 | ||
| PCT/JP2013/003331 WO2013175805A1 (en) | 2012-05-25 | 2013-05-27 | Ghrelin receptor agonists for the treatment of achlorhydria |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1204286B true HK1204286B (en) | 2015-11-13 |
| HK1204286A1 HK1204286A1 (en) | 2015-11-13 |
Family
ID=49623510
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK15104058.4A HK1203394A1 (en) | 2012-05-25 | 2013-05-27 | Ghrelin receptor agonists for the treatment of achlorhydria |
| HK15104901.3A HK1204286A1 (en) | 2012-05-25 | 2013-05-27 | Ghrelin receptor agonists for the treatment of achlorhydria |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK15104058.4A HK1203394A1 (en) | 2012-05-25 | 2013-05-27 | Ghrelin receptor agonists for the treatment of achlorhydria |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20150099709A1 (en) |
| EP (1) | EP2854810A4 (en) |
| JP (1) | JP2015517452A (en) |
| KR (1) | KR20150020602A (en) |
| CN (1) | CN104470524A (en) |
| HK (2) | HK1203394A1 (en) |
| TW (1) | TW201400506A (en) |
| WO (1) | WO2013175805A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GEP20186939B (en) | 2014-09-04 | 2018-12-25 | Healthcare Sa Helsinn | Medical treatments based on anamorelin |
| WO2016067638A1 (en) * | 2014-10-31 | 2016-05-06 | Raqualia Pharma Inc. | Tetrahydropyrazolopyridine derivatives as ghrelin receptor agonists |
| AU2015346323A1 (en) | 2014-11-12 | 2017-06-22 | Lyric Pharmaceuticals Inc. | Treatment of enteral feeding intolerance |
| WO2017083882A1 (en) * | 2015-11-11 | 2017-05-18 | Lyric Pharmaceuticals Inc. | Treatment of enteral feeding intolerance and other conditions using ulimorelin analogs |
| US20230339869A1 (en) * | 2020-09-22 | 2023-10-26 | Kyungpook National University Industry-Academic Cooperation Foundation | Use of triazole compound as ghrelin receptor agonist |
| WO2024217441A1 (en) * | 2023-04-21 | 2024-10-24 | 长春金赛药业有限责任公司 | Ghsr 1a agonist, pharmaceutical composition, and preparation method therefor and use thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5559152A (en) * | 1992-07-06 | 1996-09-24 | Komissarova; Irina A. | Pharmaceutical composition having antiacoholic activity |
| TW432073B (en) * | 1995-12-28 | 2001-05-01 | Pfizer | Pyrazolopyridine compounds |
| MXPA02010322A (en) * | 2000-04-19 | 2004-09-10 | Univ Johns Hopkins | Methods for prevention and treatment of gastrointestinal disorders. |
| ES2604943T3 (en) * | 2007-02-09 | 2017-03-10 | Ocera Therapeutics, Inc. | Ghrelin receptor macrocyclic modulators and procedures for their use |
| CN102423395A (en) * | 2011-12-13 | 2012-04-25 | 孙喜灵 | Traditional Chinese medicine for treating achlorhydria |
-
2013
- 2013-05-27 CN CN201380027503.1A patent/CN104470524A/en active Pending
- 2013-05-27 TW TW102118726A patent/TW201400506A/en unknown
- 2013-05-27 WO PCT/JP2013/003331 patent/WO2013175805A1/en not_active Ceased
- 2013-05-27 HK HK15104058.4A patent/HK1203394A1/en unknown
- 2013-05-27 KR KR20147036310A patent/KR20150020602A/en not_active Withdrawn
- 2013-05-27 EP EP13793644.9A patent/EP2854810A4/en not_active Withdrawn
- 2013-05-27 HK HK15104901.3A patent/HK1204286A1/en unknown
- 2013-05-27 US US14/400,194 patent/US20150099709A1/en not_active Abandoned
- 2013-05-27 JP JP2014555023A patent/JP2015517452A/en active Pending
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