NZ617346B2 - L-proline and citric acid co-crystals of (2s,3r,4r,5s,6r )-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol - Google Patents
L-proline and citric acid co-crystals of (2s,3r,4r,5s,6r )-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol Download PDFInfo
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- NZ617346B2 NZ617346B2 NZ617346A NZ61734612A NZ617346B2 NZ 617346 B2 NZ617346 B2 NZ 617346B2 NZ 617346 A NZ617346 A NZ 617346A NZ 61734612 A NZ61734612 A NZ 61734612A NZ 617346 B2 NZ617346 B2 NZ 617346B2
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- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002427 irreversible Effects 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 230000000366 juvenile Effects 0.000 description 1
- 230000004301 light adaptation Effects 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960000299 mazindol Drugs 0.000 description 1
- 229940035734 metformin and sulfonylureas Drugs 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 235000020825 overweight Nutrition 0.000 description 1
- 229960000464 oxandrolone Drugs 0.000 description 1
- 230000004203 pancreatic function Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001991 pathophysiological Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 230000003449 preventive Effects 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 108010070701 procolipase Proteins 0.000 description 1
- 200000000025 progressive disease Diseases 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- XRXDAJYKGWNHTQ-UHFFFAOYSA-N quipazine Chemical compound C1CNCCN1C1=CC=C(C=CC=C2)C2=N1 XRXDAJYKGWNHTQ-UHFFFAOYSA-N 0.000 description 1
- 229950002315 quipazine Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000003248 secreting Effects 0.000 description 1
- 230000000276 sedentary Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000862 serotonergic Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000001340 slower Effects 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000002336 sorption--desorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 238000004441 surface measurement Methods 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- 239000000777 urocortin Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/22—Tricarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
Provided herein is L-proline and citric acid co-crystals of (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (I-X), pharmaceutical compositions containing said co-crystals and their use in the treatment glucose-related disorders such as Type 2 diabetes mellitus and Syndrome X. disorders such as Type 2 diabetes mellitus and Syndrome X.
Description
L-PROLINE AND CITRIC ACID CO-CRYSTALS OF (2S,3R,4R,5S,6R)(3-
((5-(4-FLUOROPHENYL)THIOPHENYL)METHYL)METHYLPHENYL)
(HYDROXYMETHYL)TETRAHYDRO-2H-PYRAN-3,4,5-TRIOL
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U. S. Provisional Application
61/483,887 filed on May 9, 2011, which is incorporated by reference herein in
its entirety.
FIELD OF THE INVENTION
The present invention is directed to L-proline and citric acid co-crystals
of (2S,3R,4R,5S,6R)(3-((5-(4-fluorophenyl)thiophenyl)methyl)
methylphenyl)(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,
pharmaceutical compositions containing said co-crystals and their use in the
treatment of glucose-related disorders such as Type 2 diabetes mellitus and
Syndrome X.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a medical term for the presence of elevated blood
glucose. People with diabetes either don’t produce insulin, produce too little
insulin or do not respond to insulin, resulting in the buildup of glucose in the
blood. The most common form of diabetes is Type 2 diabetes, once referred to
as adult onset diabetes or non-insulin dependent diabetes (NIDDM), which may
account for >90% of diabetes in adults. However, as the younger population
becomes increasingly overweight or obese, Type 2 diabetes is becoming more
prevalent in teens and children. Diabetes may also refer to gestational
diabetes, Type 1 diabetes or autoimmune diabetes, once referred to as juvenile
onset diabetes and type 1 1/2 diabetes, also referred to as latent-autoimmune
diabetes in adults or LADA. Diabetes may occur because of poor dietary habits
or lack of physical activity (e.g., sedentary lifestyle), genetic mutations, injury to
the pancreas, drug (e.g., AIDS therapies) or chemical (e.g., steroid) exposure
or disease (e.g., cystic fibrosis, Down syndrome, Cushing’s syndrome). Two
PRD3210
2
rare types of genetic defects leading to diabetes are termed maturity-onset
diabetes of the young (MODY) and atypical diabetes mellitus (ADM).
Type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus or
NIDDM) is a metabolic disorder involving disregulation of glucose metabolism
and insulin resistance, and long-term complications involving the eyes, kidneys,
nerves, and blood vessels. Type 2 diabetes mellitus usually develops in
adulthood (middle life or later) and is described as the body's inability to make
either sufficient insulin (abnormal insulin secretion) or its inability to effectively
use insulin (resistance to insulin action in target organs and tissues). More
particularly, patients suffering from Type 2 diabetes mellitus have a relative
insulin deficiency. That is, in these patients, plasma insulin levels are normal to
high in absolute terms, although they are lower than predicted for the level of
plasma glucose that is present.
Type 2 diabetes mellitus is characterized by the following clinical signs
or symptoms: persistently elevated plasma glucose concentration or
hyperglycemia; polyuria; polydipsia and / or polyphagia; chronic microvascular
complications such as retinopathy, nephropathy and neuropathy; and
macrovascular complications such as hyperlipidemia and hypertension which
can lead to blindness, end-stage renal disease, limb amputation and
myocardial infarction.
Syndrome X, also termed Insulin Resistance Syndrome (IRS), Metabolic
Syndrome, or Metabolic Syndrome X, is a disorder that presents risk factors for
the development of Type 2 diabetes mellitus and cardiovascular disease
including glucose intolerance, hyperinsulinemia and insulin resistance,
hypertriglyceridemia, hypertension and obesity.
The diagnosis of Type 2 diabetes mellitus includes assessment of
symptoms and measurement of glucose in the urine and blood. Blood glucose
level determination is necessary for an accurate diagnosis. More specifically,
fasting blood glucose level determination is a standard approach used.
However, the oral glucose tolerance test (OGTT) is considered to be more
sensitive than fasted blood glucose level. Type 2 diabetes mellitus is
associated with impaired oral glucose tolerance (OGT). The OGTT thus can
aid in the diagnosis of Type 2 diabetes mellitus, although generally not
PRD3210
3
necessary for the diagnosis of diabetes (EMANCIPATOR K, Am J Clin Pathol
1999 Nov; pp665-674, Vol. 112(5):665-74; Type 2 Diabetes Mellitus, Decision
Resources Inc., March 2000). The OGTT allows for an estimation of pancreatic
beta-cell secretory function and insulin sensitivity, which helps in the diagnosis
of Type 2 diabetes mellitus and evaluation of the severity or progression of the
disease (e.g., CAUMO, A., et al., J Clin Endocrinol Metab, 2000, pp 4396-4402,
Vol. 85(11)). More particularly, the OGTT is extremely helpful in establishing
the degree of hyperglycemia in patients with multiple borderline fasting blood
glucose levels that have not been diagnosed as diabetics. In addition, the
OGTT is useful in testing patients with symptoms of Type 2 diabetes mellitus
where the possible diagnosis of abnormal carbohydrate metabolism has to be
clearly established or refuted.
Thus, impaired glucose tolerance is diagnosed in individuals that have
fasting blood glucose levels less than those required for a diagnosis of Type 2
diabetes mellitus, but have a plasma glucose response during the OGTT
between normal and diabetics. Impaired glucose tolerance is considered a prediabetic condition, and impaired glucose tolerance (as defined by the OGTT) is
a strong predictor for the development of Type 2 diabetes mellitus (HAFFNER,
S.M., Diabet Med, 1997 Aug; 14 Suppl 3:S12-8).
Type 2 diabetes mellitus is a progressive disease associated with the
reduction of pancreatic function and/or other insulin-related processes,
aggravated by increased plasma glucose levels. Thus, Type 2 diabetes
mellitus usually has a prolonged pre-diabetic phase and various
pathophysiological mechanisms can lead to pathological hyperglycemia and
impaired glucose tolerance, for instance, abnormalities in glucose utilization
and effectiveness, insulin action and/or insulin production in the prediabetic
state (GOLDBERG, R.B., Med Clin North Am ,1998 Jul; pp805-821, Vol. 82(4)).
The pre-diabetic state associated with glucose intolerance can also be
associated with a predisposition to abdominal obesity, insulin resistance,
hyperlipidemia, and high blood pressure, that is, Syndrome X (GROOP L, et al.,
Am J Hypertens, 1997 Sep;10(9 Pt 2):172S-180S; HAFFNER, S.M., J Diabetes
Complications, 1997 Mar-Apr; pp69-76, Vol. 11(2); BECK-NIELSEN, H., et al.,
Diabet Med, 1996 Sep;13(9 Suppl 6):S78-84).
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4
Thus, defective carbohydrate metabolism is pivotal to the pathogenesis
of Type 2 diabetes mellitus and impaired glucose tolerance (DIUNNEEN, S.F.,
Diabet Med, 1997 Aug; 14 Suppl 3:S19-24). In fact, a continuum from impaired
glucose tolerance and impaired fasting glucose to definitive Type 2 diabetes
mellitus exists (RAMLO-HALSTED, B.A., et al., Prim Care, 1999 Dec; pp 771-
789, Vol. 26(4)).
Early intervention in individuals at risk to develop Type 2 diabetes
mellitus, focusing on reducing the pathological hyperglycemia or impaired
glucose tolerance may prevent or delay the progression towards Type 2
diabetes mellitus and associated complications and/or Syndrome X. Therefore,
by effectively treating impaired oral glucose tolerance and / or elevated blood
glucose levels, one can prevent or inhibit the progression of the disorder to
Type 2 diabetes mellitus or Syndrome X.
Typical treatment of glucose disorders including Type 2 diabetes mellitus
and Syndrome X focuses on maintaining the blood glucose level as near to
normal as possible and includes diet and exercise, and when necessary,
treatment with anti-diabetic agents, insulin or a combination thereof. Type 2
diabetes mellitus that cannot be controlled by dietary management is treated
with oral antidiabetic agents including, but not limited to, sulfonylureas (e.g., not
limited to first generation: chlorpropamide, tolazamide, tolbutamide; second
generation: glyburide, glipizide; and third generation: glimepiride), biguanides
(e.g., metformin), thiazolidinediones (e.g., rosiglitazone, pioglitazone,
troglitazone), alpha-glucosidase inhibitors (e.g., acarbose, miglitol), meglitinides
(e.g., repaglinide), other insulin-sensitizing compounds, and /or other anti25 obesity agents (e.g., orlistat or sibutramine). For Syndrome X, the anti-diabetic
agents are additionally combined with pharmacological agents for the treatment
of the concomitant co-morbidities (e.g., antihypertensives for hypertension,
hypolipidemic agents for hyperlipidemia).
First-line therapies typically include metformin and sulfonylureas as well
as thiazolidinediones. Metformin monotherapy is a first line choice, particularly
for treating Type 2 diabetic patients who are also obese and / or dyslipidemic.
Lack of an appropriate response to metformin is often followed by treatment
with metformin in combination with sulfonylureas, thiazolidinediones, or insulin.
PRD3210
Sulfonylurea monotherapy (including all generations of drugs) is also a
common first line option. Another first line therapy choice may be
thiazolidinediones. Patients who do not respond appropriately to oral antidiabetic monotherapy, are given combinations of these agents. When glycemic
control cannot be maintained with oral antidiabetics alone, insulin therapy is
used either as a monotherapy, or in combination with oral antidiabetic agents.
These same strategies, optionally in combination with additional strategies
(e.g., anti-hypertensive) can be used for the treatment of Syndrome X.
In addition to antidiabetic agents, therapies may include add-on
treatment with anti-obesity agents such as orlistat, a pancreatic lipase inhibitor,
which prevents the breakdown and absorption of fat; or sibutramine, an
appetite suppressant and inhibitor of the reuptake of serotonin, norepinephrine
and dopamine in the brain. Other potential add-on anti-obesity agents include,
but are not limited to, appetite-suppressants acting through adrenergic
mechanisms such as benzphetamine, phenmetrazine, phentermine,
diethylpropion, mazindol, sibutramine, phenylpropanolamine or, ephedrine;
appetite-suppressant agents acting through serotonergic mechanisms such as
quipazine, fluoxetine, sertraline, fenfluramine, or dexfenfluramine; appetitesuppressant agents acting through dopamine mechanisms, eg, apomorphine;
appetite-suppressant agents acting through histaminergic mechanisms (eg,
histamine mimetics, H3 receptor modulators); enhancers of energy expenditure
such as beta-3 adrenergic agonists and stimulators of uncoupling protein
function; leptin and leptin mimetics; neuropeptide Y antagonists; melanocortin1, 3 and 4 receptor modulators; cholecystokinin agonists; glucagon-like
peptide-1 (GLP-1) mimetics and analogues (eg, Exendin); androgens (eg,
dehydroepiandrosterone and derivatives such as etiocholandione),
testosterone, anabolic steroids (eg, oxandrolone), and steroidal hormones;
galanin receptor antagonists; cytokine agents such as ciliary neurotrophic
factor; amylase inhibitors; enterostatin agonists/mimetics; orexin/hypocretin
antagonists; urocortin antagonists; bombesin agonists; modulators of protein
kinase A; corticotropin-releasing factor mimetics; cocaine- and amphetamineregulated transcript mimetics; calcitonin-gene related peptide mimetics; and
fatty acid synthase inhibitors.
PRD3210
6
There remains a need to provide an effective treatment for glucoserelated disorders such as elevated glucose levels, Type 2 diabetes mellitus,
Syndrome X, and the like. There also remains a need to provide an effective
treatment for glucose related disorders which also slows or prevents the
progression and / or development of Type 2 diabetes mellitus.
SUMMARY OF THE INVENTION
The present invention is directed to an L-proline co-crystal of a
compound of formula (I-X)
O
HO
OH
OH
OH
CH3
S
F
(I-X).
The present invention is further directed to a citric acid co-crystal of the
compound of formula (I-X)
O
HO
OH
OH
OH
CH3
S
F
(I-X).
Preferably, the L-proline and citric acid co-crystals of the compound of
formula (I-X) of the present invention are crystalline. The present invention is
further directed to processes for the preparation of the co-crystals of a
compound of formula (I-X), as herein described in more detail.
PRD3210
7
Illustrative of the invention is a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a co-crystal former of the compound of
formula (I-X), as described herein. An illustration of the invention is a
pharmaceutical composition made by mixing a co-crystal former of the
compound of formula (I-X), as described herein and a pharmaceutically
acceptable carrier. Illustrating the invention is a process for making a
pharmaceutical composition comprising mixing a co-crystal former of the
compound of formula (I-X), as described herein and a pharmaceutically
acceptable carrier.
Also described herein are methods for the treatment and / or prevention
of glucose-related disorders, said methods comprising administering to a
subject in need thereof a crystalline co-crystal of the compound of formula (I-X)
as described herein.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates a representative pXRD spectrum of L-proline (top),
the compound of formula (I-X) (bottom) and the crystalline L-proline co-crystal
of the compound of formula (I-X) (middle).
Figure 2 illustrates a representative peak-picked pXRD spectrum for the
crystalline L-proline co-crystal of the compound of formula (I-X).
Figure 3 illustrates a representative pXRD spectrum of citric acid (top),
the compound of formula (I-X) (bottom) and the crystalline citric acid co-crystal
of the compound of formula (I-X) (middle).
Figure 4 illustrates a representative peak-picked pXRD spectrum for the
crystalline citric acid co-crystal of the compound of formula (I-X).
Figure 5 illustrates a representative DSC scan for the crystalline Lproline co-crystal of the compound of formula (I-X).
Figure 6 illustrates a representative DSC scan for the crystalline citric
acid co-crystal of the compound of formula (I-X).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to co-crystals of a compound of
formula (I-X)
PRD3210
8
O
HO
OH
OH
OH
CH3
S
F
(I-X)
(also known as (2S,3R,4R,5S,6R)(3-((5-(4-fluorophenyl)thiophen
yl)methyl)methylphenyl)(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol).
More particularly, the present invention is directed to an L-proline co-crystal of
the compound of formula (I-X); and a citric acid co-crystal of the compound of
formula (I-X). In an embodiment of the present invention, the L-proline cocrystal of the compound of formula (I-X) is crystalline. In another embodiment
of the present invention, the citric acid co-crystal of the compound of formula (IX) is crystalline.
The compound of the formula (I-X) exhibits an inhibitory activity against
sodium-dependent glucose transporter, such as for example SGLT2. The
compound of formula (I-X) may be prepared according to the process as
disclosed in Nomura, S. et al., US Patent Publication, US 2005/0233988 A1,
published October 20, 2005, which is incorporated by reference herein.
Also described herein are methods for the treatment and / or prevention
of glucose-related disorders (preferably Type 2 diabetes mellitus), said
methods comprising administering to a subject in need thereof a co-crystal of
the compound of formula (I-X), as described herein.
As used herein, the notation “*” shall denote the presence of a
stereogenic center.
Where the compounds according to this invention have at least one
chiral center, they may accordingly exist as enantiomers. Where the
compounds possess two or more chiral centers, they may additionally exist as
diastereomers. It is to be understood that all such isomers and mixtures
thereof are encompassed within the scope of the present invention. Preferably,
PRD3210
9
wherein the compound is present as an enantiomer, the enantiomer is present
at an enantiomeric excess of greater than or equal to about 80%, more
preferably, at an enantiomeric excess of greater than or equal to about 90%,
more preferably still, at an enantiomeric excess of greater than or equal to
about 95%, more preferably still, at an enantiomeric excess of greater than or
equal to about 98%, most preferably, at an enantiomeric excess of greater than
or equal to about 99%. Similarly, wherein the compound is present as a
diastereomer, the diastereomer is present at an diastereomeric excess of
greater than or equal to about 80%, more preferably, at an diastereomeric
excess of greater than or equal to about 90%, more preferably still, at an
diastereomeric excess of greater than or equal to about 95%, more preferably
still, at an diastereomeric excess of greater than or equal to about 98%, most
preferably, at an diastereomeric excess of greater than or equal to about 99%.
Furthermore, some of the crystalline forms for the compounds of the
present invention may exist as polymorphs and as such are intended to be
included in the present invention. In addition, some of the compounds of the
present invention may form solvates with water (i.e., hydrates) or common
organic solvents, and such solvates are also intended to be encompassed
within the scope of this invention.
As used herein, unless otherwise noted, the term “isolated form” shall
mean that the compound is present in a form which is separate from any solid
mixture with another compound(s), solvent system or biological environment.
In an embodiment of the present invention, the L-proline co-crystal of the
compound of formula (I-X) is present in an isolated form. In another
embodiment of the present invention, the citric acid co-crystal of the compound
of formula (I-X) is present in an isolated form.
As used herein, unless otherwise noted, the term “substantially pure
form” shall mean that the mole percent of impurities in the isolated crystalline
form is less than about 5 mole percent, preferably less than about 2 mole
percent, more preferably, less than about 0.5 mole percent, most preferably,
less than about 0.1 mole percent. In an embodiment of the present invention,
the L-proline co-crystal of the compound of formula (I-X) is present as a
substantially pure form. In another embodiment of the present invention, the
PRD3210
citric acid co-crystal of the compound of formula (I-X) is present as a
substantially pure form.
Also described herein are methods for the treatment and prevention of
(preferably, the prevention of the development of) glucose related disorders
comprising administering to a subject in need thereof a therapeutically effective
amount of any of the co-crystals of the compound of formula (I-X) as herein
described.
The methods described herein are directed to the treatment and or
prevention (including delay in the progression or onset of) of “glucose-related
disorders”. As used herein, the term “glucose related disorder” shall be
defined as any disorder which is characterized by or is developed as a
consequence of elevated glucose levels. Glucose-related disorders shall
include diabetes mellitus, diabetic retinopathy, diabetic neuropathy, diabetic
nephropathy, delayed wound healing, insulin resistance, hyperglycemia,
hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of
glucose, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic
complications, atherosclerosis, or hypertension. In particular, the “glucose
related-disorder” is diabetes mellitus (type 1 and type 2 diabetes mellitus, etc.),
diabetic complications (such as diabetic retinopathy, diabetic neuropathy,
diabetic nephropathy), obesity, or postprandial hyperglycemia.
In an embodiment, the glucose related disorder is selected from the
group consisting of diabetes mellitus, diabetic retinopathy, diabetic neuropathy,
diabetic nephropathy, delayed wound healing, insulin resistance,
hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids,
hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic
complications, atherosclerosis and hypertension.
In another embodiment, the glucose related disorder is selected from the
group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, diabetic
retinopathy, diabetic neuropathy, diabetic nephropathy, obesity and
postprandial hyperglycemia. In another embodiment, the glucose related
disorder is selected from the group consisting of type 1 diabetes mellitus, type 2
diabetes mellitus, diabetic retinopathy, diabetic neuropathy, diabetic
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11
nephropathy, obesity, and delayed wound healing. In another embodiment, the
glucose related disorders is selected from the group consisting of poor glycemic
control, Type 2 Diabetes Mellitus, Syndrome X, gestational diabetes, insulin
resistance, hyperglycemia. In another embodiment, the glucose related
disorder is Type 2 diabetes mellitus.
In another embodiment, the glucose related disorder is selected from the
group consisting of elevated glucose level, pre-diabetes, impaired oral glucose
tolerance, poor glycemic control, Type 2 Diabetes Mellitus, Syndrome X (also
known as metabolic syndrome), gestational diabetes, insulin resistance, and
hyperglycemia.
Treatment of glucose related disorders may comprise lowering glucose
levels, improving glycemic control, decreasing insulin resistance and / or
preventing the development of a glucose related disorder (for example
preventing a patient suffering from impaired oral glucose tolerance or elevated
glucose levels from developing Type 2 diabetes mellitus).
As used herein, the terms “Syndrome X”, “Metabolic Syndrome” and
“Metabolic Syndrome X” shall mean a disorder that presents risk factors for
the development of Type 2 diabetes mellitus and cardiovascular disease and is
characterized by insulin resistance and hyperinsulinemia and may be
accompanied by one or more of the following: (a) glucose intolerance, (b)Type
2 diabetes mellitus, (c) dyslipidemia, (d) hypertension and (e) obesity.
As used herein, unless otherwise noted, the terms “treating”,
“treatment” and the like, shall include the management and care of a subject or
patient (preferably mammal, more preferably human) for the purpose of
combating a disease, condition, or disorder and includes the administration of a
compound of the present invention to prevent the onset of the symptoms or
complications, alleviate the symptoms or complications, or eliminate the
disease, condition, or disorder.
As used herein, unless otherwise noted, the term “prevention” shall
include (a) reduction in the frequency of one or more symptoms; (b) reduction
in the severity of one or more symptoms; (c) the delay or avoidance of the
development of additional symptoms; and / or (d) delay or avoidance of the
development of the disorder or condition.
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12
One skilled in the art will recognize that wherein methods of prevention,
are described herein, a subject in need of thereof (i.e. a subject in need of
prevention) shall include any subject or patient (preferably a mammal, more
preferably a human) who has experienced or exhibited at least one symptom of
the disorder, disease or condition to be prevented. Further, a subject in need
thereof may additionally be a subject (preferably a mammal, more preferably a
human) who has not exhibited any symptoms of the disorder, disease or
condition to be prevented, but who has been deemed by a physician, clinician
or other medical profession to be at risk of developing said disorder, disease or
condition. For example, the subject may be deemed at risk of developing a
disorder, disease or condition (and therefore in need of prevention or
preventive treatment) as a consequence of the subject's medical history,
including, but not limited to, family history, pre-disposition, co-existing
(comorbid) disorders or conditions, genetic testing, and the like.
The term “subject” as used herein, refers to an animal, preferably a
mammal, most preferably a human, who has been the object of treatment,
observation or experiment. Preferably, the subject has experienced and / or
exhibited at least one symptom of the disease or disorder to be treated and / or
prevented.
The term “therapeutically effective amount” as used herein, means that
amount of active compound or pharmaceutical agent that elicits the biological or
medicinal response in a tissue system, animal or human that is being sought by a
researcher, veterinarian, medical doctor or other clinician, which includes
alleviation of the symptoms of the disease or disorder being treated.
Optimal dosages to be administered may be readily determined by those
skilled in the art, and will vary with for example, the mode of administration, the
strength of the preparation, the mode of administration, and the advancement of
the disease condition. In addition, factors associated with the particular patient
being treated, including patient age, weight, diet and time of administration, will
result in the need to adjust dosages.
One skilled in the art will recognize that, both in vivo and in vitro trials
using suitable, known and generally accepted cell and / or animal models are
predictive of the ability of a test compound or co-therapy to treat or prevent a
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13
given disorder. One skilled in the art will further recognize that human clinical
trials including first-in-human, dose ranging and efficacy trials, in healthy
patients and / or those suffering from a given disorder, may be completed
according to methods well known in the clinical and medical arts.
As used herein, the term “composition” is intended to encompass a
product comprising the specified ingredients in the specified amounts, as well
as any product which results, directly or indirectly, from combinations of the
specified ingredients in the specified amounts.
To provide a more concise description, some of the quantitative
expressions herein are recited as a range from about amount X to about
amount Y. It is understood that wherein a range is recited, the range is not
limited to the recited upper and lower bounds, but rather includes the full range
from about amount X through about amount Y, or any amount or range therein.
To provide a more concise description, some of the quantitative
expressions given herein are not qualified with the term “about”. It is
understood that whether the term “about” is used explicitly or not, every
quantity given herein is meant to refer to the actual given value, and it is also
meant to refer to the approximation to such given value that would reasonably
be inferred based on the ordinary skill in the art, including approximations due
to the experimental and/or measurement conditions for such given value.
Examples of suitable solvents, bases, reaction temperatures, and other
reaction parameters and components are provided in the detailed descriptions
which follows herein. One skilled in the art will recognize that the listing of said
examples is not intended, and should not be construed, as limiting in any way
the invention set forth in the claims which follow thereafter.
One skilled in the art will recognize that wherein a reaction step of the
present invention may be carried out in a variety of solvents or solvent systems,
said reaction step may also be carried out in a mixture of the suitable solvents
or solvent systems.
Where the processes for the preparation of the compounds according to
the invention give rise to mixture of stereoisomers, these isomers may be
separated by conventional techniques such as preparative chromatography.
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14
The compounds may be prepared in racemic form, or individual enantiomers
may be prepared either by enantiospecific synthesis or by resolution. The
compounds may, for example, be resolved into their component enantiomers
by standard techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid
and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and
regeneration of the free base. The compounds may also be resolved by
formation of diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the compounds
may be resolved using a chiral HPLC column.
Additionally, chiral HPLC against a standard may be used to determine
percent enantiomeric excess (%ee). The enantiomeric excess may be
calculated as follows
[ (Rmoles-Smoles)/(Rmoles+Smoles) ] X 100%
where Rmoles and Smoles are the R and S mole fractions in the mixture
such that Rmoles+Smoles = 1. The enantiomeric excess may alternatively be
calculated from the specific rotations of the desired enantiomer and the
prepared mixture as follows:
ee = ([α-obs] / [α-max]) X 100.
The present invention is directed to an L-proline co-crystal of the
compound of formula (I-X), preferably a crystalline L-proline co-crystal of the
compound of formula (I-X). The present invention is further directed to a citric
acid co-crystal of the compound of formula (I-X), preferably a crystalline citric
acid co-crystal of the compound of formula (I-X).
Preparation of Crystalline L-proline and Citric Acid Co-crystals:
The L-proline and citric acid co-crystals of the compound of formula (I-X)
were prepared as part of co-crystal screening. Briefly, approximately 15 mg of
the compound of formula (I-X) was added to each well in a 48 well grinding
block along with approximately 1 molar equivalent of co-crystal-former (Lproline or citric acid, respectively) and 10µl of solvent (selected from acetone,
ethanol, isopropyl acetate, toluene, water). Six (6) individual experiments were
PRD3210
performed for each co-crystal former (5 solvents and 1 dry well). Wells were
subjected to 10 minutes of ball-mill grinding and were followed up with
immediate analysis by pXRD.
The crystalline L-proline co-crystal of the compound of formula (I-X) was
additionally prepared by slurrying the compound of formula (I-X) (~ 1g) and Lproline in acetone at a 1:1 stoichiometry.
The crystalline citric acid co-crystal of the compound of formula (I-X) was
additionally prepared by thermal crystallization of the compound of formula (I-X)
(~1 g) and citric acid in isopropyl acetate at a 1:1 stoichiometry.
Physical and Chemical Stability of L-proline and Citric Acid Co-Crystals:
The crystalline L-proline co-crystal of the compound of formula (I-X) was
tested for physical stability by storing about 10 mg of the co-crystal in 10 mL
serum crimp vials, under following conditions: (a) 5°C, sealed; (b) 25°C / 60%
RH, open; (c) 40°C, sealed; (d) 40°C / 75% RH, open; (e) 60°C, sealed; and (f)
80°C, sealed; with stability data collected at 1 day, 1 week, 2 weeks and 4
weeks. The crystalline L-proline co-crystal of the compound of formula (I-X)
was found to be physically stable up to 4 weeks under all these conditions, with
no visible color changes.
Samples of the crystalline L-proline co-crystal of the compound of
formula (I-X) being tested for physical stability, sampled at 1 day, 1 week, 2
weeks and 4 weeks, were further tested for chemical stability / degradation.
Crystalline L-proline co-crystal of the compound of formula (I-X) (~10 mg) was
diluted with a 50:50 water : acetonitrile solution (10 mL), and then further
diluted 10 fold for HPLC measurements. At 1 day, 1 week, 2 weeks and 4
weeks, all crystalline L-proline co-crystal samples appeared chemically stable.
No degradation peaks were observed and the measured % areas remained
consistent at each time point.
The crystalline citric acid co-crystal of the compound of formula (I-X) was
similarly tested for physical stability by storing about 10 mg of the co-crystal in
mL serum crimp vials, under following conditions: (a) 5°C, sealed; (b) 25°C /
60% RH, open; (c) 40°C, sealed; (d) 40°C / 75% RH, open; (e) 60°C, sealed;
PRD3210
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and (f) 80°C, sealed; with stability data collected at 1 day, 1 week, 2 weeks and
4 weeks. The crystalline citric acid co-crystal of the compound of formula (I-X)
was found to be physically stable up to 4 weeks under these conditions,
although a small amount of degradation (<0.3% on a peak basis) was observed
when stored at 25°C / 60%RH, when stored at 40°C / 75%RH and when stored
at either 60°C, or 80°C.
Samples of the crystalline citric acid co-crystal of the compound of
formula (I-X) being tested for physical stability, sampled at 1 day, 1 week, 2
weeks and 4 weeks, were further tested for chemical stability / degradation.
Crystalline citric acid co-crystal of the compound of formula (I-X) (~10 mg) was
diluted with a 50:50 water : acetonitrile solution (10 mL), and then further
diluted 10 fold for HPLC measurements. At 1 day, 1 week, 2 weeks and 4
weeks, all crystalline citric acid co-crystal samples appeared chemically stable
when stored at 5°C, sealed and 40°C, sealed. A small degradation peak was
observed in the 1 week, 2 week and 4 week, samples stored at 25°C / 60% RH,
open and samples stored at 60°C, sealed; although peak purity of these
sample remained at >99%. A few small degradation peaks were also observed
in the 1 week, 2 week and 4 week samples stored at 40°C / 75% RH, open and
80°C, sealed; although peak purity for these samples also remained >99%.
pXRD, DSC, TGA and DVS Measurements:
The crystalline L-proline co-crystal of the compound of formula (I-X) and
the crystalline citric acid co-crystal of the compound of formula (I-X) were
further characterized via powder X-ray diffraction (pXRD), dynamic scanning
calorimetry (DSC), thermogravimetric analysis (TGA and dynamic vapor
sorption / desorption (DVS).
pXRD: Powder X-ray powder diffraction patterns were obtained using
the Bruker AXS D8 Discover x-ray Diffractometer equipped with GADDSTM
(General Area Diffraction Detection System), a Bruker AXS HI-STAR Area
Detector at a distance of 15.05cm as per system calibration, a copper source
(Cu/Kα 1.54056Ǻ), automated x-y-z stage, and 0.5mm collimator. The sample
was compacted into pellet form and mounted on the x-y-z stage. A
diffractogram was acquired under ambient conditions at a power setting of
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17
40kV and 40mA in reflection mode while the sample remained stationary. The
exposure time was approximately 1 minute for each sample. The diffractogram
obtained underwent a spatial remapping procedure to account for the
geometrical pincushion distortion of the area detector then integrated along chi
from –118.8 to –61.8 degrees and 2-theta 2.1-37 degrees at a step size of 0.02
degrees with normalization set to bin normalize. In addition to using the Jade
software, diffraction patterns obtained on the Bruker machine were viewed
using EVA software.
DSC: An aliquot of the sample was weighed into an aluminum hermetic
sample pan. The sample pan was loaded into the apparatus (Q1000
Differential Scanning Calorimeter, TA Instruments), which was equipped with
an autosampler. A thermogram was obtained by individually heating the
sample at a rate of 10ºC/min from Tmin (typically room temperature) to Tmax
(typically 300 ºC) using an empty aluminum hermetic pan as a reference. Dry
nitrogen was used as a sample purge gas and was set at a flow rate of 50
ml/min. Thermal transitions were viewed and analyzed using the analysis
software provided with the instrument.
TGA: An aliquot of the sample was transferred into a platinum sample
pan. The pan was placed on the loading platform and was then automatically
loaded into the apparatus (Q500 Thermogravimetric Analyzer, TA Instruments)
using the control software. Thermograms were obtained by individually heating
the sample at 10ºC /min from Tmin (typically room temperature) to Tmax (typically
300 ºC) under flowing dry nitrogen, with a sample purge flow rate of 60ml/min
and a balance purge flow rate of 40ml/min. Thermal transitions (e.g. weight
changes) were viewed and analyzed using the analysis software provided with
the instrument.
DVS: Moisture sorption was characterized on a DVS-1 Instrument
(Surface Measurement Systems, Allentown, PA). In each case, the sample
was subject to a drying curve from ambient to 0% relative humidity (RH),
followed by two cycles of sorption (from 0% RH to 90%RH) and desorption
(from 90% RH to 0% RH) in 10% RH steps at 25°C. At each step the sample
was allowed to equilibrate at a specific %RH and thus, stabilize in terms of
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weight gained or lost prior to the instrument moving to the next step within the
method.
Crystalline L-proline Co-crystal Properties:
The crystalline L-proline co-crystal of the compound of formula (I-X) was
characterized by powder X-ray diffraction (pXRD) patterns; comparing the cocrystal patterns with the pXRD patterns of the co-crystal components, more
particularly the pXRD of the compound of formula (I-X) and the pXRD of the Lproline.
Figure 1 which follows herein, illustrates representative measured pXRD
patterns for L-proline (top), the compound of formula (I-X) (bottom) and the
crystalline L-proline co-crystal of the compound of formula (I-X) (middle).
In an embodiment, the crystalline L-proline co-crystal of the compound
of formula (I-X) may be characterized by its powder X-ray diffraction pattern,
comprising the peaks as listed in Table 1, below.
Table 1: Crystalline L-proline Co-Crystal of Compound of Formula (I-X)
No.
Position
[°2θ]
d-spacing
[Å]
Relative Intensity
[%]
1 3.76 23.50 92
2 9.52 9.29 49
3 10.99 8.05 22
4 16.99 5.22 24
17.84 4.97 100
6 18.63 4.76 92
7 19.93 4.46 26
8 20.88 4.25 20
9 21.96 4.05 44
23.42 3.80 43
11 25.92 3.44 23
12 26.77 3.33 30
Preferably, the crystalline L-proline co-crystal of the compound of
formula (I-X) is characterized by its pXRD pattern which comprises peaks
having a relative intensity greater than or equal to about 25%, preferably having
a relative intensity greater than or equal to about 40%.
In another embodiment of the present invention, the crystalline L-proline
co-crystal of the compound of formula (I-X) may be characterized by the
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19
following pXRD peaks °2θ: 3.74, 9.50, 10.98, 17.78, 18.62, 21.94, 23.43 and
26.82; as shown in the peak-picked pXRD spectrum illustrated in Figure 2.
The crystalline L-proline co-crystal of the compound of formula (I-X) was
further characterized using Differential Scanning Calorimetry (DSC), measuring
from 25°C to 300°C at 10°C / min and found to exhibit a sharp melting point at
188°C, with a shoulder at 180°C.
The crystalline L-proline co-crystal of the compound of formula (I-X) was
further characterized using Thermogravimetric Analysis (TGA), measuring from
°C to 300°C at 10°C / min and found to exhibit weight loss of 1% up to 180°C
(believed to be due to the loss of residual solvent), followed by a further 25%
weight loss up to 280°C, corresponding to the loss of 1 mole equivalent of Lproline.
The crystalline L-proline co-crystal of the compound of formula (I-X) was
further characterized using Dynamic Vapor Sorption (DVS), measuring from 0%
RH to 90%RH (2 full cycles) at 25°C. The crystalline L-proline co-crystal of the
compound of formula (I-X) was found to be hygroscopic, although no weight
gain was observed until the %RH had reached 40%. Between 40% RH and
90% RH, the co-crystal gained 12% in mass, which was lost (with some
hysteresis) during the desorption part of the measurement cycle. pXRD
collected after the DVS run (isolated at 0%RH) indicated that no irreversible
form conversion was observed with this sample.
Crystalline Citric Acid Co-Crystal Properties:
The crystalline citric acid co-crystal of the compound of formula (I-X) was
characterized by powder X-ray diffraction (pXRD) patterns; comparing the cocrystal patterns with the pXRD patterns of the co-crystal components, more
particularly the pXRD of the compound of formula (I-X) and the pXRD of the
citric acid.
Figure 3 which follows herein, illustrates representative measured pXRD
patterns for citric acid (top), the compound of formula (I-X) (bottom) and the
crystalline citric acid co-crystal of the compound of formula (I-X) (middle).
PRD3210
In an embodiment, the crystalline citric acid co-crystal of the compound
of formula (I-X) may be characterized by its powder X-ray diffraction pattern,
comprising the peaks as listed in Table 2, below.
Table 2: Crystalline Citric Acid Co-Crystal of Compound of Formula (I-X)
No.
Position
[°2θ]
d-spacing
[Å]
Relative Intensity
[%]
1 4.23 20.88 100
2 9.15 9.67 7
3 12.40 7.14 5
4 14.72 6.02 4
16.51 5.37 24
6 17.68 5.02 8
7 18.94 4.69 8
8 19.70 4.51 43
9 20.65 4.31 7
22.36 3.97 6
11 23.09 3.85 8
12 23.63 3.76 10
13 25.65 3.47 9
Preferably, the crystalline citric acid co-crystal of the compound of
formula (I-X) is characterized by its pXRD pattern which comprises peaks
having a relative intensity greater than or equal to about 5%, more preferably
having a relative intensity greater than or equal to about 10%.
In another embodiment of the present invention, the crystalline citric acid
co-crystal of the compound of formula (I-X) may be characterized by the
following pXRD peaks °2θ: about 4.2, 9.16, 12.39, 16.54, 17.69, 19.70, 23.63
and 25.66; as shown in the peak-picked pXRD spectrum illustrated in Figure 4.
The crystalline citric acid co-crystal of the compound of formula (I-X) was
further characterized using Differential Scanning Calorimetry (DSC), measuring
from 25°C to 300°C at 10°C / min and found to exhibit a single sharp melting
point at 156°C.
The crystalline citric acid co-crystal of the compound of formula (I-X) was
further characterized using Thermogravimetric Analysis (TGA), measuring from
°C to 300°C at 10°C / min and found to exhibit insignificant weight loss of
0.38% up to 155°C. This weight loss is believed to be due to the loss of
residual solvent and not an indication of the presence of a hydrated form.
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21
The crystalline citric acid co-crystal of the compound of formula (I-X) was
further characterized using Dynamic Vapor Sorption (DVS), measuring from 0%
RH to 90%RH (2 full cycles) at 25°C. The crystalline citric acid co-crystal of the
compound of formula (I-X) was found to be non-hygroscopic, with the gradual
increase of 0.5% in mass observed from 0%-80%RH, which mass was lost
again on desorption. pXRD collected after the DVS run (isolated at 0%RH)
indicated that no form conversion was observed with this sample.
The present invention further comprises pharmaceutical compositions
comprising any of the crystalline co-crystals of the compound of formula (I-X),
as described herein, with a pharmaceutically acceptable carrier.
Pharmaceutical compositions containing one or more of the compounds of the
invention described herein as the active ingredient can be prepared by
intimately mixing the compound or compounds with a pharmaceutical carrier
according to conventional pharmaceutical compounding techniques. The
carrier may take a wide variety of forms depending upon the desired route of
administration (e.g., oral, parenteral). Thus for liquid oral preparations such as
suspensions, elixirs and solutions, suitable carriers and additives include water,
glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring
agents and the like; for solid oral preparations, such as powders, capsules and
tablets, suitable carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and the like. Solid
oral preparations may also be coated with substances such as sugars or be
enteric-coated so as to modulate major site of absorption. For parenteral
administration, the carrier will usually consist of sterile water and other
ingredients may be added to increase solubility or preservation. Injectable
suspensions or solutions may also be prepared utilizing aqueous carriers along
with appropriate additives.
To prepare the pharmaceutical compositions of this invention, one or
more compounds of the present invention as the active ingredient is intimately
admixed with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques, which carrier may take a wide
variety of forms depending of the form of preparation desired for administration,
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22
e.g., oral or parenteral such as intramuscular. In preparing the compositions in
oral dosage form, any of the usual pharmaceutical media may be employed.
Thus, for liquid oral preparations, such as for example, suspensions, elixirs and
solutions, suitable carriers and additives include water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents and the like; for solid oral
preparations such as, for example, powders, capsules, caplets, gelcaps and
tablets, suitable carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and the like.
Because of their ease in administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case solid pharmaceutical
carriers are obviously employed. If desired, tablets may be sugar coated or
enteric coated by standard techniques. For parenterals, the carrier will usually
comprise sterile water, through other ingredients, for example, for purposes
such as aiding solubility or for preservation, may be included. Injectable
suspensions may also be prepared, in which case appropriate liquid carriers,
suspending agents and the like may be employed. The pharmaceutical
compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder,
injection, teaspoonful and the like, an amount of the active ingredient
necessary to deliver an effective dose as described above. The
pharmaceutical compositions herein will contain, per unit dosage unit, e.g.,
tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from
about 0.1 to about 1000 mg or any amount or range therein, and may be given
at a dosage of from about 0.01 to about 500 mg/kg/day, or any amount or
range therein, preferably from about 0.5 to about 100 mg/kg/day, or any
amount or range therein. The dosages, however, may be varied depending
upon the requirement of the patients, the severity of the condition being treated
and the compound being employed. The use of either daily administration or
post-periodic dosing may be employed.
Preferably these compositions are in unit dosage forms from such as
tablets, pills, capsules, powders, granules, sterile parenteral solutions or
suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector
devices or suppositories; for oral parenteral, intranasal, sublingual or rectal
administration, or for administration by inhalation or insufflation. Alternatively,
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23
the composition may be presented in a form suitable for once-weekly or oncemonthly administration; for example, an insoluble salt of the active compound,
such as the decanoate salt, may be adapted to provide a depot preparation for
intramuscular injection. For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose, sucrose,
sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums,
and other pharmaceutical diluents, e.g. water, to form a solid preformulation
composition containing a homogeneous mixture of a compound of the present
invention, or a pharmaceutically acceptable salt thereof. When referring to
these preformulation compositions as homogeneous, it is meant that the active
ingredient is dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective dosage forms
such as tablets, pills and capsules. This solid preformulation composition is
then subdivided into unit dosage forms of the type described above containing
from 0.01 to about 1,000 mg, or any amount or range therein, of the active
ingredient of the present invention. The tablets or pills of the novel composition
can be coated or otherwise compounded to provide a dosage form affording
the advantage of prolonged action. For example, the tablet or pill can comprise
an inner dosage and an outer dosage component, the latter being in the form of
an envelope over the former. The two components can be separated by an
enteric layer which serves to resist disintegration in the stomach and permits
the inner component to pass intact into the duodenum or to be delayed in
release. A variety of material can be used for such enteric layers or coatings,
such materials including a number of polymeric acids with such materials as
shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention
may be incorporated for administration orally or by injection include, aqueous
solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured
emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or
peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include synthetic
PRD3210
24
and natural gums such as tragacanth, acacia, alginate, dextran, sodium
carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
The method of treating glucose-related disorders described herein may
also be carried out using a pharmaceutical composition comprising any of the
compounds as defined herein and a pharmaceutically acceptable carrier. The
pharmaceutical composition may contain between about 0.01 mg and about 1000
mg of the compound, or any amount or range therein; preferably about 0.1 mg to
about 500 mg of the compound, and may be constituted into any form suitable for
the mode of administration selected. Carriers include necessary and inert
pharmaceutical excipients, including, but not limited to, binders, suspending
agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
Compositions suitable for oral administration include solid forms, such as pills,
tablets, caplets, capsules (each including immediate release, timed release and
sustained release formulations), granules, and powders, and liquid forms, such as
solutions, syrups, elixers, emulsions, and suspensions. Forms useful for
parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered
in a single daily dose, or the total daily dosage may be administered in divided
doses of two, three or four times daily. Furthermore, compounds for the present
invention can be administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to those of
ordinary skill in that art. To be administered in the form of a transdermal delivery
system, the dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic pharmaceutically
acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover,
when desired or necessary, suitable binders; lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable binders
include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth
or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,
PRD3210
sodium acetate, sodium chloride and the like. Disintegrators include, without
limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms in suitably flavored suspending or dispersing agents such
as the synthetic and natural gums, for example, tragacanth, acacia, methyl5 cellulose and the like. For parenteral administration, sterile suspensions and
solutions are desired. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is desired.
To prepare a pharmaceutical composition of the present invention, a
compound of formula (I) as the active ingredient is intimately admixed with a
pharmaceutical carrier according to conventional pharmaceutical compounding
techniques, which carrier may take a wide variety of forms depending of the
form of preparation desired for administration (e.g. oral or parenteral). Suitable
pharmaceutically acceptable carriers are well known in the art. Descriptions of
some of these pharmaceutically acceptable carriers may be found in The
Handbook of Pharmaceutical Excipients, published by the American
Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
Methods of formulating pharmaceutical compositions have been
described in numerous publications such as Pharmaceutical Dosage Forms:
Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by
Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications,
Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms:
Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by
Marcel Dekker, Inc.
The crystalline co-crystals of the compound of formula (I-X) of this
invention may be administered in any of the foregoing compositions and
according to dosage regimens established in the art whenever treatment of
glucose-related is required.
The daily dosage of the products may be varied over a wide range from
about 0.01 to about 1,000 mg per adult human per day, or any amount or range
therein. For oral administration, the compositions are preferably provided in the
form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0,
PRD3210
26
100, 150, 200, 250 and 500 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
Preferably, the crystalline co-crystal of the compound of formula (I-X) is
administered at a dosage level of from about 0.01 mg/kg to about 500 mg/kg of
body weight per day, or 0.01 mg/kg to about 200 mg/kg of body weight per day,
or any amount or range therein. Preferably, the range is from about 0.01 to about
50 mg/kg of body weight per day, or any amount or range therein, more
preferably, from about 0.05 mg/kg to about 10 mg/kg, or any amount or range
therein, more preferably, from about 1 to about 5 mg/kg of body weight per day,
or any amount or range therein. In an embodiment, an effective amount of the
crystalline co-crystal of the compound of formula (I-X) is supplied at a dosage
level of 10 mg, 25 mg, 50 mg, 100 mg, 150 mg or 300 mg, or any amount or
range therein. The crystalline co-crystals of the compound of formula (I-X) may
be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those
skilled in the art, and will vary with the particular compound used, the mode of
administration, the strength of the preparation, the mode of administration, and
the advancement of the disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight, diet and time of
administration, will result in the need to adjust dosages.
One skilled in the art will recognize that, both in vivo and in vitro trials
using suitable, known and generally accepted cell and / or animal models are
predictive of the ability of a test compound to treat or prevent a given disorder.
One skilled in the art will further recognize that human clinical trials
including first-in-human, dose ranging and efficacy trials, in healthy patients
and / or those suffering from a given disorder, may be completed according to
methods well known in the clinical and medical arts.
The following Examples are set forth to aid in the understanding of the
invention, and are not intended and should not be construed to limit in any way
the invention set forth in the claims which follow thereafter.
Example 1
Crystalline L-proline Co-Crystal of Compound of Formula (I-X)
PRD3210
27
The compound of formula (I-X) (100mg) was added to a wig-L-bug vial
along with L-proline (26.30mg) (1:1.1 molar equivalent API:CCF), a grinding
ball and acetone (20µl). The wig-L-bug was subjected to 10 minutes of
grinding. After milling the recovered solid was confirmed to be the expected
crystalline L-proline co-crystal of the compound of formula (I-X) by pXRD.
Example 2
Crystalline L-proline Co-Crystal of Compound of Formula (I-X)
The compound of formula (I-X) (50.18mg) was added to a 4ml conical
vial along with L-proline (13.15mg) (1:1.1 molar equivalent API:CCF), followed
by acetone (2 mL). The capped vial was heated briefly with a heat gun. White
solid material precipitated rapidly from the solution and was collected and
confirmed to be the expected crystalline L-proline co-crystal of the compound of
formula (I-X) by pXRD.
Example 3
Crystalline Citric Acid Co-Crystal of Compound of Formula (I-X)
The compound of formula (I-X) (100mg) was added to a wig-L-bug vial
along with citric acid (43.83mg) (1:1.1 molar equivalent API:CCF), a grinding
ball and isopropyl acetate (20µl). The wig-L-bug was subjected to 10 minutes
of grinding. After milling the recovered solid was confirmed to be the expected
crystalline citric acid co-crystal of the compound of formula (I-X) by pXRD.
Example 4
Crystalline Citric Acid Co-Crystal of Compound of Formula (I-X)
The compo und of formula (I-X) (50.72 mg) was added to a 4ml conical
vial along with citric acid (21.83mg) (1:1.1 molar equivalent API:CCF), followed
by isopropyl acetate (1 mL). The capped vial was heated with heat gun to
completely dissolve the solid materials. As no crystallization was observed on
cooling, the cap was opened and the solvent allowed to evaporate slowly. After
2 days (after approximately 20% solvent reduction) seeds of the desired
material were added to the saturated solution and a white solid crystalline
material precipitated within a few hours. The isolated material was confirmed
to be the expected crystalline citric acid co-crystal of the compound of formula
(I-X) by pXRD.
Example 5
PRD3210
28
Solid, Oral Dosage Form – Prophetic Example
As a specific embodiment of an oral composition, 100 mg of the
crystalline L-proline co-crystal of the compound of formula (I-X), prepared as
described herein is formulated with sufficient finely divided lactose to provide a
total amount of 580 to 590 mg to fill a size O hard gel capsule.
Example 6
Solid Oral Dosage Form – Prophetic Example
As a specific embodiment of an oral composition, 100 mg of the
crystalline citric acid co-crystal of the compound of formula (I-X), prepared as
described herein is formulated with sufficient finely divided lactose to provide a
total amount of 580 to 590 mg to fill a size O hard gel capsule.
While the foregoing specification teaches the principles of the present
invention, with examples provided for the purpose of illustration, it will be
understood that the practice of the invention encompasses all of the usual
variations, adaptations and/or modifications as come within the scope of the
following claims and their equivalents.
Claims (8)
1. An L-proline co-crystal of a compound of formula (I-X) O HO OH OH OH CH3 S F (I-X). 5
2. The L-proline co-crystal as in Claim 1, comprising the following pXRD peaks °2θ: 3.74, 9.50, 10.98, 17.78, 18.62, 21.94, 23.43 and 26.82, wherein the pXRD peaks are measured using Cu/Kα λ 1.54056A° radiation.
3. The L-proline co-crystal as in Claim 1, wherein the co-crystal exhibits a 10 melting point of 188°C, as measured by DSC.
4. A citric acid co-crystal of a compound of formula (I-X) O HO OH OH OH CH3 S F (I-X). 15
5. The citric acid co-crystal as in Claim 4, comprising the following pXRD peaks °2θ: 4,2, 9.16, 12.39, 16.54, 17.69, 19.70, 23.63 and 25.66, wherein the pXRD peaks are measured using Cu/Kα λ 1.54056A° radiation. PRD3210 30
6. The citric acid co-crystal as in Claim 4, wherein the co-crystal exhibits a melting point of about 156°C, as measured by DSC.
7. An L-proline co-crystal of a compound of formula (I-X) as claimed in 5 claim 1 substantially as herein described with reference to any example thereof.
8. A citric acid co-crystal of a compound of formula (I-X) as claimed in claim 4 substantially as herein described with reference to any example 10 thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161483887P | 2011-05-09 | 2011-05-09 | |
US61/483,887 | 2011-05-09 | ||
PCT/US2012/037062 WO2012154812A1 (en) | 2011-05-09 | 2012-05-09 | L-proline and citric acid co-crystals of (2s, 3r, 4r, 5s, 6r )- 2- (3- ((5- (4-fluorophenyl)thiophen-2-yl) methyl) -4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ617346A NZ617346A (en) | 2015-03-27 |
NZ617346B2 true NZ617346B2 (en) | 2015-06-30 |
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